Prognostic value of moderate or massive ascites in patients with advanced gastric cancer
- Authors:
- Published online on: January 22, 2024 https://doi.org/10.3892/ol.2024.14249
- Article Number: 116
Abstract
Introduction
Stomach cancer accounts for over 1,000,000 cases annually worldwide. It is the fourth leading cause of cancer and the fifth leading cause of mortality (1). Recent studies show that the five-year overall survival (OS) of patients undergoing endoscopic resection or laparoscopy-assisted distal gastrectomy for gastric cancer is 89.0-98.2% (2,3). However, the long-term outcomes of patients with advanced or unresectable gastric cancer remain poor. Despite recent advances in chemotherapeutics, the median OS was reported to be 13.1-17.45 months when patients with unresectable advanced gastric cancer received immunotherapy plus chemotherapy (4,5).
A study from the Netherlands reported a median OS of four months in gastric cancer patients with peritoneal metastasis (6). Intraperitoneal paclitaxel, in addition to systemic chemotherapy, was developed to improve their outcomes; however, the median OS in patients undergoing intraperitoneal paclitaxel with systemic chemotherapy was not found superior to that of patients undergoing systemic chemotherapy alone (17.7 months vs. 15.2 months, P=0.08) in the PHOENIX-GC trial (7). In clinical settings, the presence of massive ascites can impair activities of daily living, resulting in poor prognosis. Additionally, many clinical trials exclude gastric cancer patients with massive ascites caused by peritoneal metastasis, suggesting that data from clinical studies may not reflect the clinical course of patients with peritoneal metastasis.
Therefore, this study aimed to examine whether the presence or degree of ascites in advanced gastric cancer influenced prognostic value using real-world data.
Patients and methods
Patients
We retrospectively included 124 advanced gastric cancer patients who were diagnosed or treated at Fukuchiyama City Hospital from April 2009 to March 2020. We assessed patient characteristics, including blood chemical analysis at diagnosis, age, sex, and Eastern Cooperative Oncology Group Performance Status (ECOG-PS). We also assessed clinicopathological characteristics such as macroscopic type, location, histological type, human epidermal growth factor receptor 2 (HER2) status, liver metastasis, bone metastasis, and the presence and degree of ascites. The histological type was classified as intestinal or diffuse type according to the Lauren classification (8). Blood chemical analysis included the following items: white blood cell count, hemoglobin, platelet count, total protein, albumin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), C-reactive protein (CRP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR). We also assessed psoas muscle mass index (PMI) as a sarcopenia index (9). The calculation of PMI was performed as described previously (10). We also collected the data on the treatment and chemotherapy regimens. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Fukuchiyama City Hospital (approval no. 2-64). An opt-out method was conducted to obtain informed consent because this was a retrospective study.
Assessment of ascites and overall survival
The degree of ascites was assessed using computed tomography at diagnosis and classified as none, small (within the pelvic cavity), moderate (beyond the pelvic cavity), or massive (extending throughout the abdominal cavity), based on the classification used in previous studies (Fig. 1) (7,11,12). The overall survival (OS) rate was evaluated from the date of computed tomography examination to the last follow-up date or date of death. We compared the OS to the presence or amount of ascites.
Uni- and multivariate Cox proportional hazards analyses were conducted to identify predictors of OS in patients with advanced gastric cancer. The variables included age, sex, ECOG-PS, macroscopic type, histological type, HER2 status, liver metastasis, bone metastasis, ascites, moderate or massive ascites, ALP, LDH, CEA, CA19-9, NLR, PMI, and chemotherapy. The cut-off values for ALP, LDH, CEA, and CA19-9 were defined using the upper limit of the normal ranges. The cut-off values for PMI were defined using medians in the male and female (10). We compared the clinical features of patients with moderate or massive ascites and those without moderate or massive ascites.
Statistical analysis
Statistical analysis was performed using the IBM SPSS Statistics 27 (IBM Japan, Tokyo, Japan) or R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at P<0.05. Continuous variables are presented as medians and ranges, and comparisons were conducted using the Mann-Whitney U test. Categorical variables are expressed as numbers and percentages, and comparisons were performed using the χ2 test or Fisher's exact test. The OS rate was evaluated using Kaplan-Meier survival curves and the log-rank tests. Cox proportional hazards model analysis was used to estimate hazard ratio (HR) and 95% confidence interval (CI). Significant variables in the univariate analysis were included in the multivariate analysis.
Results
Clinicopathological characteristics of advanced gastric cancer
Table I presents the clinicopathological characteristics. The median age was 73, and the proportion of males was 66.9%. The median follow-up period was 232.5 days, and 112 patients (90.3%) died. The ratio of Borrmann type III or IV in the macroscopic type was 51.6%. Regarding the histological type, the percentage of the intestinal type was 45.2%, while that of the diffuse type was 53.2%. In this study, 43.5% of the patients had ascites of whom 20.2% had moderate or massive ascites. The median PMI was 4.69 in males, and 3.39 in females.
Table II presents the laboratory findings and treatment pattern of patients with advanced gastric cancer. Regarding tumor markers, the median CEA level was 5.4 ng/ml, whereas the median CA19-9 level was 34.6 ng/ml. For the inflammatory markers, the median NLR was 3.91. Regarding treatment, 40 patients (32.3%) received best supportive care, 84 (67.7%) underwent chemotherapy. As for the first-line chemotherapy regimen, 38 (30.6%) patients received cisplatin-based chemotherapy, 30 (24.2%) received oxaliplatin-based chemotherapy, 9 (7.3%) received fluoropyrimidine monotherapy, 5 (4.0%) received taxane-based chemotherapy, while 2 (1.6%) did in other institutions.
Clinical outcomes with respect to ascites
Fig. 2 shows the OS according to the staging of ascites. The median OS was 294.0 days (95% CI, 182.0-406.0 days) in patients without ascites, 216.0 days (95% CI, 0.0-454.3 days) in patients with small ascites, 345.0 days (95% CI, 0.0-808.8 days) in patients with moderate ascites, and 51.0 days (95% CI, 31.3-70.7 days) in patients with massive ascites (P=0.132).
Fig. 3A shows the OS based on the presence of ascites. The median OS was 294.0 days (95% CI, 182.0-406.0 days) in patients without ascites, and 136.0 days (95% CI, 17.3-254.7 days) in patients with ascites (P=0.116). The cumulative one-year, and two-year OS rates in patients without ascites were 43.5 and 20.2%, respectively, whereas those in patients with ascites were 29.1 and 13.6%, respectively. Fig. 3B shows the OS according to moderate or massive ascites. The median OS was 289.0 days (95% CI, 204.0-374.0 days) in patients without moderate or massive ascites, and 127.0 days (95% CI, 3.0-251.0 days) in patients with moderate or massive ascites (P=0.027). The cumulative one-year, and two-year OS rates in patients without moderate or massive ascites were 39.5 and 20.9%, respectively, whereas those in patients with moderate or massive ascites were 28.0 and 4.0%, respectively.
Predictors of overall survival in patients with advanced gastric cancer
Table III shows the predictors of OS in patients with advanced gastric cancer. In univariate analysis, age ≥80 (HR, 2.243; 95% CI, 1.503-3.347; P<0.001), ECOG-PS ≥2 (HR, 3.277; 95% CI, 2.049-5.238; P<0.001), diffuse type (HR, 1.551; 95% CI, 1.051-2.289; P=0.027), moderate or massive ascites (HR, 1.650; 95% CI, 1.053-2.586; P=0.029), ALP >321 (HR, 1.569; 95% CI, 1.053-2.336; P=0.027), LDH >245 (HR, 1.535; 95% CI, 1.039-2.267; P=0.031), NLR >5 (HR, 2.187; 95% CI, 1.479-3.232; P<0.001), and chemotherapy (HR, 0.145; 95% CI, 0.091-0.231; P<0.001) were determined to be predictive factors. In multivariate analysis, diffuse type (HR, 1.532; 95% CI, 1.002-2.343; P=0.049), moderate or massive ascites (HR, 2.153; 95% CI, 1.301-3.564; P=0.003), and chemotherapy (HR, 0.189; 95% CI, 0.101-0.352; P<0.001) were significant predictive factors for OS.
Clinical features of patients with moderate or massive ascites and those without moderate or massive ascites
Table IV shows comparative clinical features between patients with moderate or massive ascites and those without it. Gastric cancer showing Borrmann type III or IV was significantly higher in those with moderate or massive ascites compared with those without moderate or massive ascites (76.0% vs. 45.5%, P=0.012). In contrast, no significant differences were observed regarding age, sex, ECOG-PS, tumor location, histological type, and HER2 status. Regarding laboratory findings, hemoglobin concentration was significantly higher in the patients with moderate or massive ascites than those without moderate or massive ascites (12.3 g/dl vs. 10.4 g/dl, P=0.020). Furthermore, the serum CEA level was significantly lower in patients with moderate or massive ascites than those without moderate or massive ascites (3.4 ng/dl vs. 7.3 ng/dl, P=0.020). As for chemotherapy, the presence or absence of treatment with first- and second-line chemotherapy was not significantly different.
 | Table IV.Clinical features of patients with moderate or massive ascites and those without moderate or massive ascites. |
Discussion
In this study, we assessed clinicopathological factors, including the degree of ascites, to determine predictive factors in patients with advanced gastric cancer. The OS of patients with moderate or massive ascites was significantly lower than that of patients without moderate or massive ascites. Furthermore, multivariate analysis revealed that diffuse type, moderate or massive ascites, and chemotherapy were pivotal prognostic factors for OS. Collectively, we observed that moderate or massive ascites could influence OS in patients with advanced gastric cancer in a clinical setting.
Previous studies have shown that the presence of ascites or peritoneal metastases is a pivotal prognostic factor in patients with advanced gastric cancer who are undergoing chemotherapy (13–15). A prognostic index consisting of the ECOG-PS, number of metastatic sites, prior gastrectomy, and serum ALP level has been established and validated in advanced gastric cancer using phase III study data (16,17). In clinical settings, patients with advanced gastric cancer who occasionally present with massive ascites cannot receive systemic chemotherapy because of impaired activities of daily living or inadequate oral intake. Absence of chemotherapy, in addition to malignant ascites itself, may worsen the outcomes of such patients. Accordingly, we aimed to evaluate the prognostic factors of advanced gastric cancer, including patients who did not receive chemotherapy.
We determined that age ≥80, ECOG-PS ≥2, diffuse type, moderate or massive ascites, elevated ALP, elevated LDH, elevated NLR, and no chemotherapy were poor prognostic factors in the univariate analysis. Prognostic scoring models in advanced gastric cancer have revealed that malignant ascites and peritoneal metastasis are critical parameters for predicting OS (13–15,18). In contrast, another study showed that peritoneal metastasis is not associated with OS (16). The study used the clinical trial data, in which patients with ascites beyond the pelvic cavity were excluded (19). This may explain why peritoneal metastasis could not influence OS in the study. However, we encountered patients with abdominal distention due to ascites in the clinical setting. Indeed, 20.2% of patients in this study presented with moderate or massive ascites. Our results imply that that moderate or massive ascites could be a more effective prognostic factor than ascites alone. For serum indicators, serum ALP level has been reported to be a predictive factor of OS in previous studies (13–17,20), and serum LDH level was also a prognostic factor in some studies (18,20). The NLR, an inflammatory biomarker, has been recognized as a prognostic factor for solid tumors, including gastric cancer (20–23). Collectively, our data suggest that ALP, LDH, and NLR may influence OS in patients with advanced gastric cancer, as previously reported.
Diffuse type, moderate or excessive ascites, and chemotherapy were the pivotal prognostic factors in multivariate analysis. These findings imply that moderate or massive ascites at diagnosis could influence the OS in patients with advanced gastric cancer.
In this study, the ECOG-PS, or the ratio of patients undergoing first- and second-line chemotherapy did not differ between patients with moderate or massive ascites and those without moderate or massive ascites. In contrast, the NLR and CRP levels tended to be higher in patients with moderate or massive ascites, suggesting carcinomatous peritonitis. Collectively, the poor OS in patients with moderate or massive ascites may be due to systemic inflammation caused by carcinomatous peritonitis. In addition, we determined that the proportion of the macroscopic type showing Borrmann type III or IV was higher in patients with moderate or massive ascites. A previous study revealed that macroscopic type III or IV was pivotal in detecting peritoneal metastases in gastric cancer (24). These findings imply that the macroscopic type was associated with peritoneal metastases. Hemoglobin concentration was significantly higher in the patients with moderate or massive ascites. This finding suggests that intravascular dehydration might occur in patients with moderate or massive ascites. Furthermore, the serum CEA level was significantly lower in patients with moderate or massive ascites. The reason for the difference remains unknown. However, the sensitivity of CEA for peritoneal metastasis was 19% (25). Thus, the serum CEA level may not reflect malignant ascites or peritoneal metastasis.
This study had some limitations. First, this was conducted at a single center with a retrospective design; thus, a multicenter prospective study is needed to ascertain our findings. Second, our study included 124 advanced gastric cancer patients. It is difficult to generalize our findings due to the small number of patients. Third, all cases with ascites were not proven to have peritoneal metastases on histological examination. Indeed, peritoneal metastases were not confirmed by histological examinations in five of 25 cases showing moderate or excessive ascites, although peritoneal metastases were clinically diagnosed. Fourth, only Japanese patients with advanced gastric cancer were registered. Therefore, these results should be validated in other populations.
Using real-world data, our study determined that moderate or massive ascites at diagnosis could influence OS in advanced gastric cancer.
Acknowledgements
Not applicable.
Funding
This work was supported by a Grant-in-Aid for Early-Career Scientists from the Japanese Society for the Promotion of Science KAKENHI (grant no. 22K16051) to Naoto Iwai.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
NI, TOh, TOk, KO, HS, MKK, TTs, JS, KK, TD, KI, OD, NY, KU, TI, TTa, HK and YI contributed to the study's conception and design. Data collection and analysis were performed by NI, TOh, TOk, KO, HS, MKK, TTs and JS. NI, TOh, and TOk confirm the authenticity of all the raw data. All analyses were supervised by KK, TD, KI, OD, NY, KU, TI, TTa, HK and YI. The first draft of the manuscript was written by NI and all authors commented on previous versions. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Fukuchiyama City Hospital (approval no. 2-64). An opt-out method was conducted to obtain informed consent because this was a retrospective study.
Patient consent for publication
An opt-out method was conducted to obtain informed consent.
Competing interests
All authors declare that they have no competing interests.
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