Abstract
Background/Aim: This study aimed to evaluate the clinical impact of the Naples Prognostic Score (NPS) in patients with gastric cancer and to clarify the potential of the NPS as a nutritional and inflammation evaluation system. Patients and Methods: This study included 158 patients who underwent curative treatment for gastric cancer between 2005 and 2020. The prognosis and clinical pathological parameters of the high-NPS (NPS >2) and low-NPS (NPS=0, 1) groups were analyzed. Results: The overall survival (OS) rates at 3 and 5 years were 86.7% and 77.7%, respectively, in the low-NPS group and 55.4% and 47.4%, respectively, in the high-NPS group. There were significant differences in OS between the two groups. Uni- and multivariate analyses demonstrated that the NPS was an independent prognostic factor for OS (HR=2.495, 95%CI=1.240-5.451). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 82.1% and 76.0%, respectively, in the NPS-low group, and 43.8% and 36.6% in the NPS-high group. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor for RFS (HR=2.739, 95%CI=1.509-4.972). When the first site of recurrence was compared between the low-NPS group and high-NPS group, there were significant differences in peritoneal recurrence (8.7% vs. 34.3%, p=0.001) and hematologic recurrence (5.6% vs. 21.9%, p=0.004). Conclusion: The NPS was a significant prognostic factor in patients with gastric cancer who received curative treatment. The NPS may be a promising biomarker for the treatment and management of gastric cancer.
Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related death in the world (1, 2). Gastrectomy with D2 lymphadenectomy and perioperative adjuvant treatment are standard treatments for locally advanced GC (3-5). Recently, the perioperative nutritional status and inflammation status have been shown to affect postoperative surgical complications, continuation of adjuvant treatment, and the occurrence of adverse events associated with adjuvant treatment (6-8). Furthermore, the perioperative nutritional status and inflammation status also affect long-term oncological outcomes (9, 10). Currently, several scoring systems have been developed to evaluate the nutritional and perioperative inflammatory status, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and albumin/C-reactive protein ratio (CAR) (11-13). While each score has a clinical impact on oncological outcomes there is no consensus on the optimal cutoff value for each score. Additionally, studies on the interaction between the nutritional status and inflammation scores have been limited.
The Naples Prognostic Score (NPS) was developed as a new scoring system for some malignancies (14-16). The NPS is calculated using serum albumin, serum cholesterol, NLR, and LMR and may therefore reflect host systemic inflammation and malnutrition. However, few studies have evaluated the clinical impact of the NPS in patients with gastric cancer.
The aim of the present study was to evaluate the clinical impact of the NPS in patients with gastric cancer and also clarify its potential application as a nutritional and inflammation evaluation system.
Patients and Methods
Patients. Consecutive patients who underwent curative resection for gastric cancer at Yokohama City University from 2005 to 2020 were selected based on medical records. The following inclusion criteria were applied: 1) histologically confirmed adenocarcinoma; 2) clinical stage I-III disease according to the 15th edition of the general rules of the Japanese Gastric Cancer Association for gastric cancer (17); 3) curative gastrectomy performed as primary treatment for gastric cancer; and 4) complete resection (R0 resection) of gastric cancer, including radical lymph node dissection.
Surgical procedure and adjuvant treatment. Each patient underwent gastrectomy with either D1+ or D2 nodal dissection. S-1-based adjuvant chemotherapy was administered for patients with pathological stage II or III disease (18, 19).
Measurement of the NPS. The NPS was calculated based on the following four parameters: serum albumin (normal: ≥4 g/dl), total cholesterol (normal: >180 mg/dl), LMR (normal: ≤2.96), and NLR (normal: >4.44). The patients were divided into three groups. Patients with normal values for all four parameters were assigned a score of 0, those with one or two altered values were assigned to group 1, and those with three or four altered values were assigned to group 2 (20).
Follow-up. Follow-up examinations were conducted at outpatient clinics. The patients underwent hematological tests (including measurements of tumor markers) and physical examinations at least every three months for five years. Additionally, every three months during the first three years after surgery and every six months until five years after surgery, patients underwent computed tomography (CT) examinations.
Evaluations and statistical analyses. The chi-square test was used to assess the significance of the variances between the NPS and clinicopathological factors. Overall survival and recurrence-free survival curves were calculated using the Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Cox proportional hazards model. Statistical significance was set at p<0.05. All statistical analyses were conducted using SPSS (v27.0 J Win; IBM, Armonk, NY, USA). The present study was approved by the institutional review board of Yokohama City University.
Results
Patients background. The present study included 158 patients. The median age was 70 years (range=32-87 years). One hundred thirteen patients were male and 45 patients were female. Based on previous study results and 3- and 5-year survival rates, we divided patients into low-NPS (NPS=0 and 1) and high-NPS (NPS=2) groups. When comparing the patient backgrounds of the low- and high-NPS groups, there were significant differences in T status, lymph node metastasis status, and lymphovascular invasion status (Table I). The incidence of aggressive tumor status was significantly higher in the NPS-high group than in the NPS-low group.
Comparison of survival rates stratified by patient characteristics.
Survival analysis. In the present study, the 3- and 5-year overall survival rates were 86.7% and 77.7%, respectively, in the NPS-low group and 55.4% and 47.4% in the NPS-high group. Figure 1 shows the overall survival (OS) curves. There were significant differences in OS between the two groups. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor (HR=2.495, 95%CI=1.240-5.451) (Table II). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 82.1% and 76.0%, respectively, in the NPS-low group and 43.8% and 36.6% in the NPS-high group. Figure 2 shows the RFS curves. There were significant differences in RFS between the two groups. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor (HR=2.739, 95%CI=1.509-4.972) (Table III). When the first recurrence sites between the NPS-low and NPS-high groups were compared, there were significant differences in peritoneal recurrence (8.7% vs. 34.3%, p=0.001) and hematological recurrence (5.6% vs. 21.9%, p=0.004) (Table IV).
Overall survival in patients with gastric cancer in the high-Naples Prognostic Score (NPS) group and low-NPS group.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
Recurrence-free survival in patients with gastric cancer in the high-Naples Prognostic Score (NPS) group and low-NPS group.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.
Patterns of recurrence according to Naples Prognostic Score.
Perioperative clinical course in the NPS-low group and NPS-high group. When comparing the perioperative clinical course, the rates of perioperative complications were as follows: postoperative surgical complications (NPS-low vs. NPS-high: 34.1% vs. 43.8%; p=0.311), pneumonia (5.6% vs. 6.3%; p=0.880), anastomotic leakage (4.8% vs. 6.3%; p=0.732), abdominal abscess (4.0% vs. 3.1%; p=0.824), and pancreatic fistula (8.7% vs. 6.3%; p=0.648). There were no significant differences between the two groups.
With regard to the clinical course of postoperative adjuvant chemotherapy, the percentage of patients who required adjuvant chemotherapy in the NPS-low and NPS-high groups was 23.8% and 59.3%, respectively (p<0.001), while the percentage of patients who received adjuvant chemotherapy was 83.3% and 68.4% (p=0.223). The percentage of cases in which adjuvant chemotherapy was terminated due to adverse events was 37.5% in the NPS-low group and 30.0% in the NPS-high group (p=0.290).
Discussion
The aim of the present study was to clarify the clinical impact of the NPS as a prognostic factor for patients with gastric cancer who received curative treatment. The main finding was that the NPS was a significant prognostic factor. Additionally, the NPS affected recurrence patterns. Therefore, the NPS is a promising biomarker for the treatment and management of patients with gastric cancer.
In the present study, patients with higher NPS values had a poorer prognosis, and the hazard ratio of a higher NPS was 2.495 (95%CI=1.240-5.451). Similar results have been reported in previous studies.
Xiong et al. evaluated the clinical impact of the NPS in 1,283 patients with gastric cancer who underwent curative surgery (21). They reported that the NPS was associated with age, sex, body mass index, and tumor progression. The patients in the NPS-high group were older and showed a male predominance, lower body mass index, and aggressive tumor status. The median OS in the NPS 0, NPS 1, and NPS 2 groups was 67.7, 52.5, and 35.7 months, respectively. The NPS was closely related to OS. The univariate and multivariate analyses showed that the HR for OS was 2.21 (95%CI=1.27-3.31) for NPS 1 and 3.45 (95%CI=1.43-5.17) for NPS 2 in their study. They concluded that the NPS represents a simple and useful rating system that can independently predict the survival of patients with gastric cancer undergoing surgery. Xiong et al. evaluated the clinical impact of the NPS in 231 patients with adenocarcinomas of the esophagogastric junction who underwent curative surgery (22). The median OS and RFS was 60.0 and 56.4 months, respectively, in the NPS 0 group, 49.2 and 43.6 months in the NPS 1 group, and 43.6 and 32.4 months in NPS 2 group. The NPS score was closely related to OS and RFS. The univariate and multivariate analyses showed that the HR for OS was 1.85 (95%CI=1.22-2.43) for NPS 1 and 3.29 (95%CI=2.16-3.17) for NPS 2 in their study. They concluded that the NPS represents a simple and useful rating system that can independently predict the survival of patients with adenocarcinoma of the esophagogastric junction who undergo surgery.
There are several possible explanations as to why the NPS affects the survival of patients with gastric cancer. One possibility is that the NPS affects the response to chemotherapy. Lieto et al. evaluated the clinical relationship between the NPS and tumor regression grade in 59 patients with gastric cancer who received FLOT-4-based neoadjuvant chemotherapy and curative gastrectomy (23). They reported that total or partial tumor regression was observed in 100% of the patients in the NPS 0 group, 50% of the patients in the NPS 1 group, and 17.4% of the patients in the NPS 2 group. They concluded that evaluation of the NPS in patients with gastric cancer undergoing multimodal treatment may be useful both in selecting patients who will benefit from preoperative chemotherapy and for changing immuno-nutritional conditions in order to improve the patient’s reaction to the tumor. Although there was no relationship between the perioperative clinical course of adjuvant chemotherapy, such as the introduction of adjuvant chemotherapy, and the occurrence of adverse events from the adjuvant chemotherapy, in the present study, the NPS might have some clinical impact on the efficacy of perioperative adjuvant treatment. Therefore, future studies should focus on this issue. The second possible reason is that the NPS affects postoperative surgical complications. Although there was no relationship between the NPS and the occurrence of postoperative surgical complications in the present study, some reports suggest a clinical relationship between the NPS and postoperative surgical complications in gastrointestinal cancers. Lin et al. clarified the clinical relationship between the NPS and postoperative surgical complications in 2,182 patients with gastric cancer who underwent curative surgery (24). They found that the incidence of severe postoperative surgical complications was significantly higher in the high-NPS group (NPS >1) than in the low-NPS group (NPS ≤1) (3.7% vs. 1.8%, p=0.008). They concluded that the NPS is an important tool for assessing the risk of severe postoperative surgical complications. Galizia et al. evaluated the clinical relationship between the NPS and postoperative surgical complications in 468 patients with colorectal cancer who received curative treatment (20). The incidence of postoperative surgical complications increased with worsening NPS. The incidence of postoperative surgical complications was 8-10% in the NPS-low group and 14-21% in the NPS-high group. Considering this, NPS status might have some clinical impact on the occurrence of postoperative surgical complications in gastrointestinal cancer surgery.
To utilize the NPS in general practice, it is necessary to set an optimal cutoff value for each element. First, the NPS was proposed by Galizia et al. using patients with colorectal cancer and is composed of the preoperative LMR, NLR, serum albumin, and total cholesterol (20). These elements include the nutritional and inflammatory status. However, previous studies have suggested that there are some differences in the nutritional and immune statuses of patients with colorectal and gastric cancers. Therefore, future studies should reconstruct the New-NPS according to the nutritional status of patients with gastric cancer. Wang et al. evaluated the new-NPS as a prognostic factor in patients with gastric cancer (25). In that study, the cutoff values used were 2.37 for NLR, 3.10 for LMR, 4.25 for albumin, and 156.81 for total cholesterol. They demonstrated that the New-NPS constructed according to the nutritional and immune status of patients with gastric cancer has a certain applicable value and is worthy of clinical application. Further studies are needed to clarify the optimal cutoff value for each element.
Study limitations. First, it was a retrospective, single-center study. Therefore, there may have been a selection bias. Second, the present study patients were treated between 2005 and 2020. Therefore, there may be a time bias. The perioperative adjuvant treatment was changed from 2005 to 2020. Initially, surgery alone was the standard of care; S-1 adjuvant therapy was introduced in 2007, and S-1 and docetaxel adjuvant therapy for stage III gastric cancer was introduced in 2015. Therefore, a validation study is required.
In conclusion, we found that the NPS was a significant prognostic factor for patients with gastric cancer who received curative treatment. NPS may be a promising biomarker for the treatment and management of gastric cancer.
Acknowledgements
This study was supported by JSPS KAKENHI (Grant Number 21K08688). This study was supported in part by the nonprofit organization of the Yokoyama Surgical Research Group (YSRG).
Footnotes
Authors’ Contributions
TA and AK contributed substantially to this concept and design. TA, IH, YM, MT, TM, KH, KK1 (Keisuke Kazama), KK2 (Keisuke Komori), MN, SK, IH, and HC contributed substantially to data acquisition, analysis, and interpretation. TA, MN, SS, MT, HT, AS, TA, KS, SY, NK, TO, NY, and YR were involved in drafting and critically revising the manuscript for important intellectual content. TA and AK approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received October 31, 2023.
- Revision received November 28, 2023.
- Accepted November 29, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
