Clinicopathological and Prognostic Significance of Platelet-Lymphocyte Ratio (PLR) in Gastric Cancer: A Meta-Analysis


 Background: Systemic inflammatory parameters, such as the elevator PLR (platelet-lymphocyte ratio), have been found to be associated with the prognosis in gastric cancer (GC); however, the results remain controversial. So we aimed to evaluate the prognostic role of the PLR in gastric cancer by conducting this meta-analysis.
Methods: We performed a systematic literature search in PubMed, Embase and the Cochrane Library. The hazard ratio (HR) /Odds Ratio (OR) and its 95% confidence (CI) of survival outcomes and clinicopathological parameters were calculated.
Results: A total of 38 studies (39 cohorts) with 23,317 GC patients were included in the final meta-analysis. The pooled results showed that elevated PLR was significantly associated with poor overall survival (OS) (HR: 1.37, 95% CI: 1.25-1.51, p < 0.001; I2= 82.10%, Ph < 0.001) and disease-free survival (DFS) (HR 1.52, 95%CI 1.22–1.90, P< 0.001, I2= 88.6%, Ph< 0.001) of GC patients. Furthermore, patients with elevated PLR had a higher risk of lymph node metastasis (OR = 1.33, 95% CI: 1.03–1.70, p=0.027), serosal invasion (T3 +T4) (OR = 1.58, 95% CI: 1.09–1.31, p=0.017) and increased advanced stage (III+IV) (OR = 1.37, 95% CI: 1.00–1.89, p=0.050).
Conclusions: This meta-analysis demonstrated that elevated PLR was a prognostic factor for poor OS and DFS, and associated with clinicopathological parameters in patients with GC.

statistical analysis was performed with STATA software version 14.0 (STATA Corporation, College Station, TX, USA). Results with p <0.05 were considered statistically significant, and all the results were two sided.

Study characteristics
A total of 38 studies (39 cohorts) [7, 11-13, 17-50] with 23,317 GC patients were included in the final meta-analysis. As in Fan Feng's study [37], the GC patients were included in a training set and a validation set independently, therefore, the two cohorts were extracted separately and named as Fan Feng1 and Fan Feng2. The selection process of the included studies according to the PRISMA guidelines was shown in Figure 1. We summarized the characteristics of the included studies in Table 1. Among them, 6 studies were from Europe and the United States, 32 studies were from Asia. The patients from 25 studies had surgery treatment, while 3 studies of advanced-stage patients had chemotherapy strategy, and 6 studies of patients had mixed treatment (including chemotherapy, surgery, radiotherapy, targeted therapy and supportive care). The cut-off values of PLR used by the included studies varied from 10.1 to 350. Therefore, we selected PLR = 150 to divide the included studies in subgroup analysis. All studies with NOS scores≥6 were regarded as high quality studies.

PLR and clinicopathological parameters of GC
To further explore the impact of PLR on the clinicopathological parameters in GC, we extracted the patient amounts from parts of included studies in PLR high and PLR low groups according to the TNM stage, tumor differentiation, depth of invasion, tumor size, tumor location, lymph node metastasis. As shown in Table 3, in comparison to low PLR groups, the high PLR groups had a higher risk of lymph node metastasis (n =14, OR = 1.33, 95% CI: 1.03-1.70, p=0.027), serosal invasion (T3 +T4) (n =12, OR = 1.58, 95% CI: 1.09-1.31, p=0.017) and increased advanced stage (III+IV) (n =14, OR = 1.37, 95% CI: 1.00-1.89, p=0.050). Whereas elevated PLR value was not shown to be associated with tumor size, tumor differentiation and tumor location.

Sensitivity analysis
We performed sensitivity analysis for the OS by removing every single study at a time to check if individual study influenced the results. The results of the sensitivity analysis were shown in Figure 4. The corresponding pooled HRs did not substantially change, which indicated that the results of our meta-analysis were stable and robust.

Publication bias
Begg's funnel plot and the Egger's linear regression test were performed to assess publication bias. The figure of the Begg's funnel plot did not show any evidence of obvious asymmetry ( Figure 5). Egger's tests (P=0.087) indicated that no publication bias was found in this meta-analysis either.

Discussion
The current meta-analysis was designed to investigate the prognostic value of patients was conducted and showed that PLR was not a reliable predictor for OS in patients with GC, while another meta-analysis including 13 studies with 6,280 patients indicated that elevated PLR could be a significant prognostic biomarker for poor OS [80,81]. Thus, the prognostic value of the PLR remains inconclusive in gastric cancer. So we conducted this update meta-analysis to evaluate the prognostic role of the PLR in gastric cancer.
The current study, including 38 studies (39 cohorts) with 23,317 GC patients, not only investigated the prognostic value of PLR for OS and DFS, but also explored the associations between PLR and clinicopathological characteristics of GC. This analysis demonstrated that elevated PLR lead to a higher risk of lymph node metastasis, increased serosal invasion (T3+T4) risk and advanced stage (III+IV) in patients with gastric cancer. Although the specific mechanism is still incompletely understood, our results are in accordance with other studies about various cancers, such as pancreatic ductal adenocarcinoma, hepatocellular carcinoma and colorectal cancer [82][83][84][85][86]. Previous meta-analysis did not find significantly association between PLR and OS or DFS in GC, maybe because of the limited studies included [80,81]. Our meta-analysis including much more studies suggested that elevated There were some limitations need to be addressed in this meta-analysis. Firstly, the inclusion criteria of this meta-analysis were constrained to studies published in English language only. So publication bias cannot be excluded. Secondly, almost all the included studies were retrospective, which could contribute to more susceptible to some biases. Fortunately, the asymmetry in the funnel plots showed no significantly publication bias, thus maintaining the substantial consistency of the results. Thirdly, different cut-off values of PLR were used in each study which could contribute to the heterogeneity. Subgroup analysis was conducted based on the different PLR cut-off values, while the results were not substantially change.
Therefore, further well-designed studies, especially randomized controlled trials (RCTs) are needed to determine the most appropriate cut-off value of PLR to predict the complication risks and survival outcomes in patients with GC.

Conclusions
In conclusion, we found that elevated PLR was a prognostic factor for poor OS and DFS in GC patients. Furthermore, elevated PLR was correlated with a higher risk of serosal invasion, lymph node metastasis and advanced TNM stage (III+IV) in gastric cancer. The present study suggests that the PLR could provide reliable information before treatment for patients with gastric cancer. Declarations Ethics approval and consent to participate All the data supporting our findings in this paper were freely downloaded from the PubMed, EMBASE, the Cochrane Library.
No ethical approval or written informed consent for participation was required.

Consent for publication Not applicable.
Availability of data and materials All data for this study are publicly available and are ready for the public to download at no cost from the official websites of the PubMed, EMBASE, the Cochrane Library. There is no need to have the formal permission to use data for this study. The sources and data robustness have been described in the section of "Methods".
Competing interests The authors declare that they have no competing interests.    Figure 1 The flow diagram of publications selection.

Figure 2
The forest plot between elevated PLR and OS in GC patients.

Figure 3
The forest plot between elevated PLR and DFS in GC patients.

Figure 4
Sensitivity analysis of PLR for OS in GC patients.

Figure 5
Begg's funnel plot of publication bias test for OS in GC patients.