Abstract
Background/Aim: The prognostic nutritional index (PNI) has been reported as an immunonutritional index that can easily evaluate nutritional status and immunocompetence from blood tests. The purpose of this study was to investigate the usefulness of PNI as a prognostic factor in postoperative gastric cancer patients. Patients and Methods: In this retrospective cohort study, we evaluated 258 patients with pStage I-III gastric cancer who underwent radical resection at Yokohama City University Hospital, from 2015 to 2021. To examine the association with prognosis, we analyzed clinicopathological factors including PNI (<47/≥47), age (<75/≥75), sex (male/female), depth (pT1/≥pT2), lymph node metastasis (pN+/pN−), lymphatic invasion (ly+/ly−), vascular invasion (v+/v−), histological type (enteric/spread) and postoperative complications. Results: In univariate analysis, PNI (p<0.001), depth of tumor invasion (p<0.001), lymph node involvement (p<0.001), age (p=0.002), lymphatic invasion (p<0.001), vascular invasion (p<0.001), and postoperative complications (p=0.003) were associated with overall survival. In multivariate analysis, PNI (HR=2.100, 95% confidence interval 1.225-3.601, p=0.007), tumor invasion, lymph node metastasis, and postoperative complications were shown as poor prognostic factors for overall survival. Conclusion: PNI is an independent prognostic factor for overall and recurrence-free survival in postoperative gastric cancer patients. PNI could be implemented in clinical practice to identify patients at higher risk for poor outcomes.
Gastric cancer is a cause of significant morbidity and mortality; 1,000,000 cases are diagnosed, and 800,000 cases die every year (1). The current standard of care for gastric cancer is surgery and adjuvant therapy. However, many patients experience recurrence after curative resection for gastric cancer (2). Therefore, it is crucial to identify the prognostic factors for recurrence after surgical techniques and adjuvant chemotherapy. Previous studies have investigated various prognostic factors and their efficacy has been reported (3-5). Lien YC et al. reported that preoperative serum albumin level was associated with resectability and survival in patients with adenocarcinoma of the gastric cardia (3). Preoperative nutritional status and the patient’s immune status may be prognostic factors for the patient’s long-term survival in various malignancies (3-5).
In this study, we focused on the prognostic nutritional index (PNI) as a prognostic indicator for gastric cancer. PNI has been widely used, owing to its efficiency, simplicity, and convenience, in assessing the preoperative condition and in predicting the surgical risk for gastrointestinal malignancy patients (6-8). PNI is calculated by the serum albumin concentration and the peripheral blood lymphocyte count. PNI was originally intended for use in patients with Stage IV and V (9); however, recently, it has been used more widely for preoperative risk assessment in many malignancies (10). In the present study, we aimed to investigate the validity of PNI for predicting prognosis in postoperative gastric cancer patients.
Patients and Methods
Patients. A total of 258 patients with gastric cancer underwent gastrectomy in the Department of Surgery in Yokohama City University Hospital, Yokohama, Japan, between January 2015 and December 2021. The clinicopathological factors were determined according to the Japanese classification of Gastric Carcinoma: 3rd English edition (11). Patients with gastric adenocarcinoma classified as clinical stage I-III were undergone curative resection.
Surgery and adjuvant treatment. Total gastrectomy and distal, proximal, or partial gastrectomy were performed. Generally, pathological stage II was treated with S-1 monotherapy, whereas pathological stage III was treated with S-1 plus docetaxel or capecitabine plus oxaliplatin.
Methods. According to Onodera et al., the PNI was calculated preoperatively for each case using the following formula: 10 × serum albumin value (g/dl) + 0.005 × lymphocyte count in peripheral blood (9). We performed univariate analysis using Cox proportional hazards model using nine clinical background factors [PNI (>47/≤47), age (>75/≤75 years), sex (male/female), tumor depth (T1, T2 or T3), tumor location (upper, middle, lower), lymphatic invasion (negative/positive), venous invasion (negative/positive), histology (intestinal/diffuse), and postoperative complications (no/yes)] to investigate their association with overall survival (OS) and recurrence-free survival (RFS). The Cox proportional hazard model was used to perform univariate and stepwise multivariate survival analyses.
Statistical analysis. Categorical variables are presented as frequency and percentage (%). The chi-square test, Student’s t-test, and the Mann–Whitney test were used to compare the groups. Survival curves were created by the Kaplan–Meier method, and a log-rank test was used to analyze the equality of survival curves. The univariate and multivariate hazard ratios were calculated using the Cox proportional hazard model. All significant variables in the univariate analysis were used for backward stepwise multivariate models. A p-value of less than 0.05 was considered to be statistically significant. The statistical analyses were performed using the SPSS software program, version 27.0 (SPSS, Chicago, IL, USA).
Results
Patients’ background. A total of 258 patients with gastric cancer were evaluated in this study. The patients were aged from 31 to 88 years old, 183 were males and 75 females. Total gastrectomy and distal, proximal, or partial gastrectomy were performed on 66, 180 and 11 patients, respectively. D1+ and D2 lymph node dissection was performed on 139 and 112 patients, respectively. The cutoff value for the PNI was set to 47 according to the OS rate and previous reports (Table I). All patients were classified into two groups, PNI low group [<47; n=75 (29.1%)] and PNI high group [≥47; n=183 (70.9%)]. The analysis of the patient background characteristics revealed statistically significant differences between the PNI low and PNI high groups regarding the following variables: median age (67 years vs. 72 years, p=0.001), preoperative hemoglobin (11.0 g/dl vs. 13.5 mg/dl, p=0.001), and preoperative C-reactive protein (0.14 mg/dl vs. 0.92 mg/dl, p<0.001).
Comparison of overall survival rates stratified by patient characteristics.
Survival analysis. The 9 clinicopathologic factors based on patient, operation, and tumor findings were analyzed as shown in Table I. OS was compared between the groups using the log-rank test. There were significant differences in age (<75 vs. ≥75), site of tumor (upper, middle, lower third), UICC T status (T1 vs. T2 to T3), lymph node metastasis, lymphatic invasion, vascular invasion, postoperative surgical complication and the PNI (<47 vs. ≥47). The 3-year and 5-year OS rates were 85.0 and 79.1% in the PNI high group and 60.4% and 44.7% in the PNI-low group, respectively (both p<0.001). The OS curves are shown in Figure 1. Univariate analyses for overall survival revealed that the PNI, age, T status, lymph node metastasis, lymphatic invasion, vascular invasion, and postoperative surgical complication were significantly associated with OS. According to the multivariate analysis (Table II), the PNI was an independent predictor of OS [hazard ratio (HR)=3.452, 95% confidence interval (CI)=2.042-5.836, p=0.007]. Univariate analyses for RFS demonstrated that PNI also was a significant prognostic factor (Table III). The 5-year RFS rate was significantly higher in the PNI-high compared to the PNI-low group (79.1% vs. 50.7%, p<0.001) (Figure 2). The PNI was selected for the final multivariate analysis model [HR=1.962, 95% CI=1.185-3.249, p=0.009] (Table III). Between PNI high and low groups, a comparison of patterns of recurrence showed a significant difference in peritoneal recurrence (7.7% vs. 20.0% p=0.004) (Table IV).
The overall survival in the prognostic nutritional index (PNI) high group and the PNI low group.
Uni- and multi-variate Cox proportional hazards analysis of clinicopathological factors for overall survival.
Uni- and multi- variate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.
The recurrence-free survival in the prognostic nutritional index (PNI) high group and the PNI low group.
Patterns of recurrence according to prognostic nutritional index.
Perioperative clinical course. The total rates of postoperative surgical complications in the PNI high and low groups did not differ to a statistically significant extent (38.7% vs. 37.7%, p=0.889). Similarly, no difference was observed regarding anastomosis leakage (12.0% vs. 7.1%, p=0.223), pneumonia (4.0% vs. 6.6%, p=0.564), and abdominal abscess (2.7% vs. 3.3%, p=1.00) between two groups. The proportion of Stage II and III cases was significantly lower in the high PNI group, compared to that in the low PNI group [58/183 (32%) vs. 49/75 (65%), p<0.001]. Among stage II and III cases, the introduction rate of postoperative adjuvant chemotherapy rate was higher in the PNI high group, compared to the PNI low group (77% vs. 47%, p=0.0395).
Discussion
The aim of the present study was to examine the usefulness of PNI as a predictor of prognosis in postoperative gastric cancer patients. The major finding was that PNI was an independent predictive factor of OS in postoperative gastric cancer patients, suggesting that PNI should be included in the routine assessment of gastric cancer patients.
In the present study, PNI was an effective prognostic factor for patients with gastric cancer undergoing gastrectomy. Similar results were observed in the previous studies. Jiang et al. evaluated the clinical impacts of PNI in gastric cancer patients undergoing total gastrectomy. They used a cutoff value of 46 to divide patients into PNI-low and high group and demonstrated that the 5-year OS rate of the PNI-low group was significantly lower than that of the PNI-high group (6). Nozoe et al. investigated the prognostic value of PNI in patients with gastric cancer who had been treated by resection and lymph node dissection. In their report, the mean PNI value (49.7) of the study population was set as the cutoff to divide patients into high and low groups. They demonstrated that the 5-year OS rates in PNI-low group were significantly lower than those in PNI high group (67.7% vs. 86.5%) (8). In all these studies, the 5-year survival rates varied; however, they were significantly lower in the PNI-low group than in the PNI-high group.
There are several reasons that could explain the correlation between PNI and prognosis found in this study. First, PNI status may have affected the rate of induction of postoperative adjuvant therapy. In our study, the proportion of patients requiring postoperative chemotherapy who actually received it was significantly lower in PNI-low. It is possible that patients with low PNI had a lower rate of induction of postoperative therapy and did not benefit from postoperative therapy. In fact, the rate of peritoneal recurrence was higher in patients with low PNI. Previous studies have shown that adjuvant S-1 therapy reduces peritoneal recurrence, and a low PNI may prevent the induction of S-1, resulting in peritoneal recurrence and a poor prognosis (12, 13). Further investigation is needed to determine what causes may influence the initiation of adjuvant therapy. The second reason is that differences in perioperative complication rates between high and low PNI groups may have influenced prognosis. Previous studies demonstrated the clinical relation between PNI and postoperative complications (14, 15). So far, the patients with postoperative complications have had significantly poor prognosis. For example, Hirahara et al. evaluated the PNI status and postoperative complications after laparoscopic gastrectomy cancer patients. They found that PNI low patients had more postoperative complications and poor survival. Therefore, PNI status is associated with the occurrence of postoperative complications and, consequently, with poor prognosis.
The optimal cutoff value of the PNI to predict the long-term outcomes remains unclear. Nozoe et al. have demonstrated that the PNI provides useful information regarding the clinical outcomes of patients with gastric carcinoma. They used the mean PNI value (49.7) among the study patients as a threshold to divide PNI low and high groups and showed that the 5-year survival rate was significantly lower in patients with low PNI than in patients with high PNI (67.7% vs. 86.5%, p<0.001) (8). Migita et al. have set the cutoff value at 48, with a sensitivity and specificity for predicting the 5-year OS were 82.3% and 57.9%, respectively. They showed the 5-year OS rate was 85.7 % in the PNI-high group and 54.5% in the PNI-low group (p<0.001) (7). Nan Jiang et al. performed a ROC curve analysis and found PNI 46 as the optimal cutoff value. When the PNI was 46, the Youden index was maximal. They demonstrated that the 5-year OS rate was 54.1% in the PNI-high group and 21.1% in the PNI-low group (p<0.001) (6). Each report used similar cutoffs and the results were comparable. In the present study, the cutoff was set at 47 based on previous literature, and similar findings were obtained.
This study had several limitations. First, it was the retrospective study. A randomized, prospective cohort, multicenter study is needed to generalize the results and clarify the underlying mechanisms. Second, the study was limited to Asian patients, most of which were Japanese. It is not clear whether the results of this study will be applicable to a multiracial population. Third, the number of patients was small. Therefore, several possible factors such as postoperative therapy and peritoneal metastases could not be included in the multivariate analysis. Finally, the optimal cutoff value for true PNI remains unclear. In this study, we defined a PNI of less than 47 as clinically significant nutritional immune status.
Conclusion
PNI was an independent prognostic factor for overall and recurrence-free survival in postoperative patients with gastric cancer. Its implementation in clinical practice to identify patients at higher risk for poor outcomes may contribute to improved survival of postoperative gastric cancer patients.
Footnotes
Authors’ Contributions
TI, TA made substantial contributions to the concept and design. TI, TA, made substantial contributions to the acquisition of data and the analysis and interpretation of the data. TI, TA, MJ, KK, MF, HK, SS, HT, AT, HC, KH, MN, IH, YM, KS, TO, AS, NY and YR were involved in drafting the article or revising it critically for important intellectual content. TI, TA, HC, KS, TO, AS, NY and YR give their final approval of the version to be published.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received January 26, 2023.
- Revision received March 21, 2023.
- Accepted April 6, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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).