Abstract
Background/Aim
This study aimed to clarify the prognostic and predictive factors of patients with gastric cancer (GC) who are peritoneal lavage cytology positive and negative for other distant metastasis.
Patients and Methods
Consecutive patients were selected from the database of Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Department of Gastric Surgery, Tokyo, Japan, according to the following criteria: i) histologically-proven gastric adenocarcinoma; ii) patients who underwent macroscopically curative gastrectomy for gastric cancer as a primary treatment; and iii) a diagnosis of peritoneal washing cytology positive (CY1) disease with no distant metastasis between 2005 and 2025.
Results
A total of 89 patients were eligible for the present study. One-, three- and five-years overall survival (OS) rates of the whole cohort were 68.6%, 41.2%, and 21.3%. Medina survival time was 22.2 months (range=11.3-33.1 months). In the prognostic analysis for OS in the CY positive patients with GC who were negative for other distant metastasis, postoperative chemotherapy status was one of the independent prognostic factors [hazard ratio (HR)=2.228, 95% confidence interval (CI)=1.330-3.734]. One-, three- and five-years OS rates of the patients with postoperative adjuvant chemotherapy were 81.1%, 46.3%, and 33.9%, while that of patients without postoperative chemotherapy were 47.6%, 32.9%, and 4.7% (p=0.001). In addition, the prognostic analysis for OS in the CY positive patients GC who were negative for other distant metastasis and received postoperative chemotherapy, lymph node metastasis status was an independent significant prognostic factor in multivariate analysis (HR=6.312, 95% CI=1.476-26.996, p=0.013).
Conclusion
Postoperative chemotherapy improved the survival of CY positive patients with GC who were negative for other distant metastasis. In addition, lymph node metastasis status was an independent prognostic factor for CY positive patients with GC who were negative for other distant metastasis and received postoperative chemotherapy.
Keywords: Gastric cancer, survival, peritoneal lavage cytology
Introduction
Gastric cancer (GC) is the fifth most prevalent cancer and fourth leading cause of cancer-related death worldwide (1, 2). The prognosis of GC is gradually improving due to introduction of minimally invasive surgery, improvement of perioperative care, and development of therapies including immune-check point inhibitor (ICI) (3-5). However, approximately 20-50% of patients with GC diagnosed with stage IV at the time of diagnosis, the prognosis of stage IV GC is still poor (6-8). Median overall survival (OS) is 12-16 months, and 5-years OS of stage 4 GC is less than 5% (9-11). Thus, to improve the survival of GC, it is necessary to develop more aggressive treatment strategies for stage IV GC.
Peritoneal lavage cytology (CY) is widely used to determine the stage of various malignancies including GC. Abdominal free cancer cells are detected in 20-60% of peritoneal washing samples in patients with GC (12-14). Both Japanese Classification of Gastric Cancer and TNM classification by the Union for International Cancer Control classified GC with CY positive as stage IV GC (15, 16). Recently, some reports and one phase II study demonstrated that gastrectomy with postoperative adjuvant chemotherapy improved survival of CY positive patients with GC who were negative for other distant metastasis (17-19). Based on those findings, upfront surgery and systemic chemotherapy of S-1 is frequently selected for CY1-only patients in daily clinical practice. However, no confirmative studies have been reported thus far.
Considering these, we evaluated the clinical impacts of postoperative adjuvant chemotherapy for CY positive patients with GC who are negative for other distant metastasis. In addition, we also clarify the prognostic factor of CY positive GC patients who are negative for other distant metastasis with postoperative adjuvant chemotherapy.
Patients and Methods
Patients. Consecutive patients were selected from the database of Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Department of Gastric Surgery, Tokyo, Japan, according to the following criteria: i) histologically-proven gastric adenocarcinoma; ii) patients who underwent macroscopically curative gastrectomy for gastric cancer as a primary treatment; and iii) a diagnosis of CY1 disease with no distant metastasis between 2005 and 2025. We excluded patients who were subjected to R2 resection.
Postoperative chemotherapy. In principle, patients received S-1 chemotherapy as follows; 40 mg of S-1 per square meter of body surface area twice a day (80 mg/m2/day) for 4 weeks, followed by 2 weeks of rest as 1 course (6-week schedule) or for 2 weeks followed by 1 week of rest as 1 course (3-week schedule).
Peritoneal lavage cytology. The cytological examinations of peritoneal lavage samples were performed as recommended by the Japanese Classification of Gastric Carcinoma. Our indication for the examination was the detection of clinical ≥T2 tumors. The cytological analysis of peritoneal lavage samples was routinely performed at the time of surgical exploration using 50 ml of normal saline that had been introduced in the abdominal cavity. After gentle agitation, as much peritoneal fluid was collected as possible. Cytological smears were prepared from centrifuged deposits and were examined by an experienced pathologist after Papanicolaou staining (Hematoxylin, catalog number: 617-28-2; Merk, NJ, USA) (Eosin Y, catalog number: 039-01321; Wako Chemicals, Osaka, Japan).
Patient follow-up. At a minimum, patients receive physical examinations and hematological tests every three -twelve months for five years. Tumor marker levels [carcinoembryonic antigen (Lumipulse Presto CEA, code no. 298985; FujiRebio, Tokyo, Japan) and CA19-9 (Lumipulse Presto CA19-9, code no. 298992FujiRebio)] were checked every three-twelve month for five years. Computed tomography (CT) was performed every 6-12 months for five years. Endoscopy was performed 1, 3, and 5 years after surgery.
Evaluation and statistical analysis. The progression of tumors was evaluated using the 15th edition of the Japanese Gastric Cancer Classification. Differences between groups were analyzed using χ2 test and Mann-Whitney U-test. Univariate and multivariate logistic regression analyses were performed to identify risk factors. In the multivariate analysis, we fitted linear regression models. To select a model, we used backward elimination. Overall survival (OS) curves were calculated using the Kaplan-Meier method. Univariate and multivariate analyses of survival were conducted using a Cox proportional hazards model. Statistical significance was defined as p<0.05. All statistical analyses were conducted using SPSS (v27.0 J Win; SPSS, Chicago, IL, USA). This study was approved by the Institutional Review Board (IRB) of the Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital (IRB number; 3531).
Results
A total of 2023 patients with GC were eligible for the present study. Among these, 89 patients were CY positive but negative for other distant metastasis, 61 were male and 28 were female, and median age was 71 years (range=37-93 years). Fifty-six patients received postoperative chemotherapy, while 33 patients did not receive postoperative adjuvant chemotherapy. Among these 33 patients who did not receive postoperative chemotherapy, six patients did not receive chemotherapy due to postoperative surgical complications, five patients due to comorbidity, four patients due to age, four patients due to patients’ general condition, four patients due to their refusal, four patients due to poor oral intake after surgery, four patients due to physician’s choice, and two patients due to early recurrence. When comparing background between the patients who received chemotherapy and the patients who did not receive chemotherapy, there were differences in age (67 years old vs. 76 years old, p=0.002) and incidence of postoperative surgical complications (21.0% vs. 51.4%, p=0.002). However, other factors were almost similar between the two groups. One-, three- and five-years OS rates of the whole cohort were 68.6%, 41.2%, and 21.3%. Medina survival time was 22.2 months (range=11.3-33.1 months) (Figure 1). When comparing the OS according to each stratified factor, there were significant differences in postoperative adjuvant chemotherapy status and lymph node metastasis status (Table I). In the prognostic analysis for OS in CY positive patients with GC who were negative for other distant metastasis, postoperative adjuvant chemotherapy status and lymph node metastasis status were significant prognostic factors and histological type was the marginal significant prognostic factor in univariate analysis (Table II). In the multivariate analysis, postoperative adjuvant chemotherapy status [hazard ratio (HR)= 2.237, 95% confidence interval (CI)=1.321-3.789] and lymph node metastasis status were the independent prognostic factors (HR=2.801, 95% CI=1.101-7.125). One-, three- and five-years OS rates of the patients with postoperative adjuvant chemotherapy were 81.1%, 46.3%, and 33.9%, while those of patients without postoperative adjuvant chemotherapy were 47.6%, 32.9%, and 4.7% (p=0.001) (Figure 2). In addition, the prognostic analysis for OS in CY positive patients with GC who were negative for other distant metastasis and received postoperative chemotherapy, lymph node metastasis status and histological type were significant prognostic factors in univariate analysis (Table III). In the multivariate analysis, lymph node metastasis status was an independent prognostic factor (HR=6.312, 95% CI=1.476-26.996, p=0.013). One-, three- and five-years OS rates of the patients in the N0-N1 group were 100%, 78.8%, and 78.8%, while those of patients in the N2 or more group were 75.4%, 31.7%, and 18.1% (p=0.002) (Figure 3). Table IV shows the patterns of recurrence according to lymph node metastasis status.
Figure 1.
Overall survival of peritoneal cytology-positive gastric cancer patients who are negative for other distant metastasis.
Table I. Comparison of survival rates stratified by patient characteristics.
OS: Overall survival.
Table II. Univariate and multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival in all cohorts.
HR: Hazard ratio; 95%CI: 95% confidence interval.
Figure 2.
Comparison of overall survival between patients managed with and without adjuvant chemotherapy.
Table III. Univariate and multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival in the patients with postoperative adjuvant chemotherapy.
HR: Hazard ratio; 95%CI: 95% confidence interval.
Figure 3.
Comparison of overall survival between patients with N0 or N1 lymph node metastasis and those with ≥N2.
Table IV. Patterns of recurrence according to lymph node metastasis status.
Discussion
The aim of the present study was to evaluate the clinical impacts of adjuvant chemotherapy for CY positive patients with GC who were negative for other distant metastasis and clarify the prognostic factors of CY positive patients with GC who were negative for other distant metastasis and received adjuvant chemotherapy. We found that adjuvant chemotherapy improved the survival of CY positive patients with GC who were negative for other distant metastasis. In addition, lymph node metastasis status was an independent prognostic factor for CY positive patients with GC who were negative for other distant metastasis and received adjuvant chemotherapy. Thus, although adjuvant chemotherapy improved the survival of CY positive patients with GC who were negative for other distant metastasis, more aggressive treatment was needed to improve cytology patients with GC who were negative for other distant metastasis and N2 more lymph node metastasis.
First, we discuss the OS of CY positive patients with GC who were negative for other distant metastasis. In the present study, we found that three- and five-years OS rates of the whole cohort were 41.2% and 21.3%. Median survival time was 22.2 months (range=11.3-33.1 months). Previously, Kano et al. evaluated the survival of 125 CY positive patients with GC who were negative for other distant metastasis and received adjuvant chemotherapy (17). They found that one-, three- and five-years OS rates of the whole cohort were 64.8%, 17.3%, and 9.8%. Median survival time was 15.9 months. Moreover, Kodera et al. conducted phase II study for gastric cancer with CY1 status but no other residual disease treated with postoperative chemotherapy with S-1 (18). They found that two- and five-years OS rates were 46% and 26%. Median survival time was 705 days. Although it is difficult to directly compare OS with other clinical trials for stage IV GC, the survival of CY positive patients with GC who are negative for other distant metastasis might be relatively better survival than other stage IV patients with GC.
Second, we discuss the clinical impact of adjuvant treatment for CY positive patients with GC who were negative for other distant metastasis. In the present study, postoperative adjuvant chemotherapy improved CY positive patients with GC who were negative for other distant metastasis. In addition, postoperative adjuvant chemotherapy was one of the independent prognostic factors in CY positive patients with GC who were negative for other distant metastasis. Previously, similar results were observed in other reports. Shim et al. evaluated the clinical impacts of postoperative chemotherapy in 88 patients with GC who received radical D2 gastrectomy and had positive cytology but without gross peritoneal metastasis (19). In Shim’s study, 64 patients received postoperative chemotherapy, and 24 patients did not receive postoperative chemotherapy. When comparing OS and recurrence free survival (RFS), there were significant differences in both OS and RFS between the two groups. Median OS and RFS were 11.63 months and 25.50 months, respectively, in the patients with postoperative chemotherapy, while 12.11 months and 6.98 months respectively in patients without postoperative chemotherapy. In uni- and multivariate analysis, postoperative chemotherapy status was one of the independent prognostic factors for both OS (HR=4.37, 95% CI=2.24-8.49, p<0.001) and RFS (HR=3.76, 95% CI=1.95-7.24, p<0.001). However, although postoperative chemotherapy is needed for GC with CY1 status but no other residual disease, optimal regimen and duration of chemotherapy is unclear. Nakayama et al. retrospectively assessed whether S-1 and cisplatin treatment (SP) could improve the survival of patients with gastric cancer with CY1 status but no other residual disease, as compared to S-1 monotherapy (20). In Nakayama’s study, 44 patients were enrolled and divided in the SP (n=19) and S-1 (n=25) group. There were no significant differences between the two groups. Two-years OS, median OS, and median RFS were 52.0%, 28.2 months, and 15.6 months in the S-1 group, and 52.6%, 24.0 months, and 18.8 months in the SP group. Considering these, although combination therapy is a potential promising treatment for improving the outcome of stage IV GC according to the previous pivotal studies, stage IV GC treatment regimen might not be suitable for CY positive patients with GC who are negative for other distant metastasis. Future study need to clarify the optimal chemotherapy for CY positive patients with GC who are negative for other distant metastasis and massive lymph node metastasis.
Third, we discuss the prognostic factors of CY positive patients with GC who were negative for other distant metastasis and received adjuvant chemotherapy. In the present study, we found that pathological lymph node metastasis status was an independent prognostic factors in CY positive patients with GC who were negative for other distant metastasis. Similar results were observed in Endo‘s study (21). They clarified the prognostic factors for cytology-positive and no other distant metastasis GC. They reviewed 128 patients from six institutions between 2000-2019. In this study, 16 patients received preoperative chemotherapy, and 92 patients received postoperative chemotherapy. In the multivariate analysis for OS, lymph node metastasis status was one of the independent prognostic factors [pathological (p) N3b vs. pN0, HR=4.46, 95%CI=1.17-16.9, p=0.03). Median survival time was 71.5 months in pN0, 41.1 months in pN1, 23.1 months in pN2, 19.7 months in pN3a, and 14.4 months in pN3b, respectively. Considering the present study and previous studies, the prognosis of the patients with massive lymph node metastasis is poor and might need more aggressive chemotherapy in CY positive patients with GC who were negative for other distant metastasis patients received perioperative chemotherapy.
Limitations. First, the present study was retrospective from single institution. Thus, there might be patient selection bias. Second, there might be time bias. The present study included patient with GC from 2005 to 2025. During this period, the standard treatment for unresectable GC dramatically changed. For example, immune check point inhibitor was introduced (ICI) and ICI treatment improved the survival of metastatic GC. Moreover, molecular target agents, such as Trastuzumab and Zolbetuximab, have also been introduced and improved the survival of metastatic patients with GC (22, 23). Third, the cytology positive rate might be underestimated in the present study. In our study, we performed peritoneal washing cytology (PWC) in Douglas’ pouch. However, the sensitivity of PWC is relatively low. A previous study demonstrated that PWC in multiple cavities was more sensitive compared to that in only one cavity (24). Although there are some limitations in the present study, our study included relatively lager number of patients and incidence of CY positive patients with GC who were negative for other distant metastasis is almost similar to previous studies. Thus, our study has some clinical impact for CY positive patients with GC who are negative for other distant metastasis treatment.
Conclusion
In conclusion, postoperative chemotherapy improved the survival of CY positive patients with GC who were negative for other distant metastasis. In addition, lymph node metastasis status was an independent prognostic factor for CY positive patients with GC who were negative for other distant metastasis and received postoperative chemotherapy. To improve outcomes of CY positive patients GC who are negative for other distant metastasis, more aggressive treatment is needed to improve cytology of patients with GC who are negative for other distant metastasis and N2 more lymph node metastasis.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
Authors’ Contributions
Toru Aoyama and Haruhiko Cho made substantial contributions to the conception and design. Toru Aoyama and Kentaro Hara made substantial contributions to the acquisition of data, or the analysis and interpretation of data. Toru Aoyama and Hideaki Suematsu were involved in drafting the manuscript or revising it critically for important intellectual content. All Authors gave final approval of the version to be published. Each author participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agreed to be 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. All Authors read and approved the final manuscript.
Acknowledgements
The Authors express their sincere gratitude to Ms. Emiko Saito for her excellent data management.
Funding
None.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
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