Abstract
Background/Aim: The platelet-to-lymphocyte ratio (PLR) is a promising prognostic marker in some malignancies. The present study evaluated the clinical impact of the PLR in patients with gastric cancer who underwent curative resection. Patients and Methods: This study included 258 patients who underwent curative treatment for gastric cancer between 2005 and 2020. The prognosis and clinicopathological parameters between the high- and low-PLR statuses were analyzed. Results: The overall survival (OS) stratified by each clinical factor was compared using the log-rank test, and a significant difference was observed using a pretreatment PLR of 150. When comparing the patient backgrounds between the high-PLR (PLR≥150) and low-PLR (PLR<150) groups, there were no significant differences between the two groups. The OS rates at 3 and 5 years after surgery were significantly higher at 70.8% and 60.4%, respectively, for the high-PLR group than at 83.6% and 79.7%, respectively, for the low-PLR group. Univariate and multivariate analyses of the OS showed that the PLR was a significant prognostic factor. In addition, when comparing the first recurrence sites, there were significant differences in peritoneal recurrence. Conclusion: The PLR is a significant risk factor for gastric cancer, making it a promising prognostic factor for patients with gastric cancer.
Among the different types of cancer, gastric cancer currently ranks fourth in prevalence, and second as a cause of cancer-related death (1, 2). Advances in minimally invasive surgery, perioperative adjuvant treatment, and perioperative care have gradually improved the prognosis of gastric cancer (3-8). However, even after curative treatment, nearly 50% of patients with gastric cancer develop recurrent disease (9, 10). Accordingly, studies should be conducted to investigate prognostic factors and predictors of perioperative adjuvant treatment.
To date, several prognostic factors have been identified for gastric cancer (11). Among these, the preoperative nutritional status and systemic inflammation status have been identified as particularly promising prognostic factors. Previous studies have demonstrated that both the nutritional status and inflammation status are involved in tumor invasion and enhance metastasis (12). Furthermore, the nutritional status and systemic inflammation status interact with each other, with an elevated inflammation status leading to a poor nutritional status. Therefore, it is necessary to evaluate both the nutritional status and inflammation status as prognostic and/or predictive factors.
Recently, the platelet-to-lymphocyte ratio (PLR) has proven a promising prognostic maker in some malignancies (13, 14). Previous studies have reported that a high PLR is related to a poor prognosis. A high PLR may be closely related to a poor nutritional status and hyperinflammation status. However, few studies have clarified the clinical relationship between the PLR and gastric cancer oncological outcomes. If we could clarify the clinical impact of the PLR in gastric cancer, we might be able to introduce nutritional or anti-inflammatory treatment in the perioperative period.
The present study therefore evaluated the clinical impact of the PLR in patients with esophageal cancer who underwent curative resection.
Patients and Methods
Patients. The medical records of consecutive patients with esophageal cancer who underwent curative resection at Yokohama City University from 2005 to 2020 were retrospectively reviewed. All patients had histological diagnosis of adenocarcinoma; were judged to have clinical stage I-III disease based on the 15th edition of the general rules for gastric cancer reported by the Japanese Gastric Cancer Association (15); received curative gastrectomy as a primary treatment for gastric cancer; and received complete resection (R0) of gastric cancer with radical lymph node dissection.
Surgical procedure and adjuvant treatment. In all cases, patients received gastrectomy with nodal dissection. D1+ nodal dissection and D2 dissection were performed for patients with clinical stage IA disease and clinical stage ≥IB disease, respectively. Patients with pathological II or III disease were treated with S-1-based adjuvant chemotherapy within six weeks after surgery (16, 17).
Definition of postoperative complications (POCs). POCs were defined using the Clavien-Dindo classification. The grade 2-5 POCs that occurred during hospitalization and/or within 30 days after surgery were retrospectively determined from the patients’ records (18).
Follow-up. The patients were followed up at outpatient clinics. At least every three months for five years, the patients underwent hematological tests (including CEA and CA19-9 tumor marker level measurements) and physical examinations. In addition, every three months during the first three years after surgery and every six months until five years after surgery, the patients underwent computed tomography (CT) examinations.
Measurement of the preoperative PLR. The PLR was calculated as the serum platelet level (×104/μl) divided by the serum lymphocyte level (×102/μl) measured before surgery.
Evaluations and statistical analyses. Differences in the PLR and clinicopathological parameters were analyzed using the chi-square test. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using the Kaplan-Meier method. A Cox proportional hazards model was used to perform univariate and multivariate survival analyses. The p-value cutoff was set at p<0.05. The SPSS software program (v27.0 J Win; IBM, Armonk, NY, USA) was used for all statistical analyses. This study was approved by the IRB of Yokohama City University (IRB number: F220500063).
Results
Patients’ background characteristics. A total of 258 patients were included in this study. The median age was 70 years (range=32-88 years), 183 patients were male, and 75 patients were female. The OS stratified by each clinical factor was compared using the log-rank test, and a significant difference was observed using a pretreatment PLR of 150 (Table I). On comparing the patient backgrounds between the high-PLR (PLR≥150) and low-PLR (PLR<150) groups, significant differences were noted in the pathological T status and sex. The incidence of a ≥T2 pathological T status was 41.1% in the low-PLR group and 53.5% in the high-PLR group (p=0.046). The incidence among females was 19.9% in the low-PLR group and 41.1% in the high-PLR group (p<0.001).
Comparison of survival rates stratified by patient characteristics.
Survival analyses and recurrence patterns. All clinicopathological factors were categorized (Table II) and their prognostic significance was analyzed. In the univariate analyses for OS, the following were identified as significant: age, pathological T factor, pathological N factor, pretreatment PLR, vascular invasion, lymphatic invasion, and POCs. The pretreatment PLR was therefore included in the final multivariate analysis. In the high-PLR group, the OS rates at 3 years and 5 years after surgery (70.8% and 60.4%, respectively) were significantly lower in comparison to the low-PLR group (83.6% and 79.7%). The OS curves are shown in Figure 1. The PLR was a significant prognostic factor in the univariate analyses for RFS. The PLR was included as a significant prognostic factor in the final multivariate analysis model (Table III). In the high-PLR group, the RFS rates at 3 and 5 years after surgery (68.2% and 50.1%, respectively) were significantly lower in comparison to the low-PLR group (80.2% and 78.0%). The RFS curves are shown in Figure 2. When comparing the first recurrence sites, there were significant differences in peritoneal recurrence between the groups: 20.5% in the high-PLR group and 4.1% in the low-PLR group (p<0.001) (Table IV). In contrast, lymph node and hematological recurrences were similar between the groups.
Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
The overall survival in the esophageal cancer patients between the high-PLR (PLR≥150) and low-PLR (PLR<150) groups.
Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.
The recurrence-free survival in the esophageal cancer patients between the high-PLR (PLR≥150) and low-PLR (PLR<150) groups.
Patterns of recurrence according to platelet-lymphocyte ratio.
Postoperative clinical course of adjuvant chemotherapy and POCs. On comparing the clinical course of postoperative adjuvant chemotherapy, the incidence of patients who needed postoperative chemotherapy was 37.6% (55/146) in the low-PLR group and 50.0% (56/112) in the high-PLR group (p=0.047), showing significant differences between the two groups. In contrast, the introduction rate of postoperative adjuvant chemotherapy was similar between the low- and high-PLR groups [65.5% (36/55) vs. 58.9% (56/112), p=0.047]. In addition, the incidence of discontinuation of postoperative adjuvant chemotherapy due to adverse events was similar between the low- and high-PLR groups. Furthermore, when comparing the clinical course of POCs, there were no significant differences between the low- and high-PLR groups. The incidences of POCs [37.6% (55/146) vs. (43/112), p=0.906], postoperative pneumonia [5.5% (8/146) vs. 6.3% (7/112), p=0.793], anastomotic leakage [6.8% (10/146) vs. 10.7% (12/112), p=0.271], abdominal abscess [4.1% (6/146) vs. 1.9% (2/112), p=0.286], and pancreatic fistula [8.2% (12/146) vs. 5.4% (6/112), p=0.371] were similar between the low- and high-PLR groups.
Discussion
We demonstrated the clinical impact of the PLR in patients with gastric cancer who underwent curative treatment. The PLR was found to be a significant risk factor in gastric cancer patients. Furthermore, a high PLR was associated with peritoneal recurrence. Based on these findings, the PLR is considered to be a promising prognostic factor for patients with gastric cancer.
In the present study, the high-PLR (PLR≥150) group had a significantly poorer prognosis than the low-PLR (PLR<150) group [hazard ratio (HR)=2.254, 95% confidence interval (CI)=1.310-3.880, p=0.0003]. Furthermore, the OS rates at 3 and 5 years after surgery were significantly lower (70.8% and 60.4%, respectively) in the high-PLR group than in the low-PLR group (83.6% and 79.7%, respectively). Although limited studies have evaluated the clinical impact of the PLR in gastric cancer, similar results have been observed in previous studies.
Messager et al. clarified the prognostic value of the PLR in 153 esophageal and junctional adenocarcinoma (OJA) patients treated with neoadjuvant chemotherapy (NAC) and curative surgery (19). They demonstrated that a higher PLR was significantly associated with a poorer prognosis. The PLR was selected as an independent prognostic factor in the multivariate analysis (HR=2.47; 95%CI=1.21-5.01, p=0.012). In addition, the recurrence rate was significantly different between the low- and high-PLR groups (35.2% vs. 54.8%, p=0.046). Furthermore, Chen et al. clarified the prognostic value of the PLR in 91 patients with gastric cancer treated with NAC and curative surgery (20). They also demonstrated that a higher PLR was significantly associated with a poorer prognosis. The PLR was selected as an independent prognostic factor in the multivariate analysis (HR=0.304; 95%CI=0.123-0.752, p=0.010), findings that are consistent with our own. Therefore, the pretreatment PLR might have a clinical influence on the survival of patients with gastric cancer.
Regarding why a high pretreatment PLR is associated with poor oncological outcomes, the first possible reason is that the pretreatment PLR influences the occurrence of POCs. Although there were no clinical relationships between the PLR and POCs in the present study, previous studies have demonstrated a clinical relationship between the pretreatment PLR and POCs. Inaoka et al. investigated the risk factors of the pretreatment PLR for severe POCs in 312 patients with gastric cancer who received curative treatment (21). They defined severe POCs as Clavien-Dindo classification grade ≥II. Among 312 patients with gastric cancer, 66 (21.1%) had severe POCs. In the risk factor analysis, a high pretreatment PLR was an independent risk factor for severe POCs (odds ratio=3.32; 95%CI=1.82-6.25, p<0.001). Recent studies, including ours, have demonstrated that postoperative surgical complications affect the long-term oncological outcomes in patients with gastric cancer. Therefore, pretreatment with a high PLR leads to POCs, resulting in a poor prognosis.
The second possible reason is that the pretreatment PLR affects chemotherapy resistance or response. Lee et al. investigated the clinical impact of the PLR in predicting chemotherapy resistance in 174 patients with advanced gastric cancer who received oxaliplatin/5-fluorouracil (FOLFOX) (22). They found that the PLR was also associated with a longer PFS [5.6 months (low-PLR) vs. 3.4 months (high-PLR), p=0.006] and OS [16.9 months (low-PLR) vs. 10.9 months (high-PLR), p=0.002]. Considering these findings, a high pretreatment PLR might have some clinical impact on the perioperative clinical course. Further studies are needed to clarify the optimal mechanism between the pretreatment PLR and the perioperative clinical course.
The setting of an optimal cutoff value is essential for the introduction of the PLR in the daily clinical setting. In the current study, based on the 1-, 3-, and 5-year survival rates, we set the cutoff value of the PLR at 150. Several other cutoff values have been reported, including 160 (22), 192 (19), 162 (20), and 172 (23). There are several possible explanations for these differences, including differences in the study populations and patient background factors. For example, the populations of the present study (n=258), the study of Toyokawa et al. (n=225), and the study of Messager et al. (n=153) were composed of patients with resectable gastric cancer (23), whereas Lee et al. evaluated patients with unresectable gastric cancer (n=174). Moreover, the methods used to determine the cutoff value of the PLR were heterogeneous (e.g., our study determined the cutoff value according to the patient survival rate, whereas others determined the cutoff value based on a receiver operating characteristic curve). Third, the endpoints of each study differed. Five studies, including our study, evaluated long-term oncological outcomes, whereas two evaluated short-term oncological outcomes. These differences might have affected the choice of the PLR cutoff value. Further studies are needed to establish the optimal methods and optimal cutoff values of the PLR.
The present study was associated with several limitations, including its retrospective nature, relatively small sample size, and the fact that it was performed in a single institution. As a result, there may have been a selection bias. The possibility of a time bias should also be considered as the present study was conducted over a relatively long period (2005 to 2020), during which there were changes in perioperative adjuvant treatment and perioperative care. Based on these limitations, the results of the present study should be validated in a larger cohort.
In conclusion, the PLR is a significant risk factor in patients with gastric cancer, suggesting it to be a promising prognostic factor for patients with gastric cancer.
Acknowledgements
This work was supported by JSPS KAKENHI (grant number 21K08688). This study was supported, in part, by the non-profit organization Yokoyama surgical research group (YSRG).
Footnotes
Authors’ Contributions
TA and YM contributed substantially to the concept and design. TA, KH, KK1 (Keisuke Kazama), KK2 (Keisuke Komori), HT, AT, SW, HT, IH, and HC made substantial contributions to the acquisition, analysis, and interpretation of the data. TA, JM, KS, MI, TO, AS, AK, NY, and YR were involved in drafting the article and revising it critically for important intellectual content. TA and YM approved the final version to be published.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received July 20, 2023.
- Revision received August 18, 2023.
- Accepted August 28, 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).
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.