Elevated Baseline Circulating Platelet-to-Lymphocyte Ratio And Survival In Stage (cid:0) Gastric Cancer Patients: A Meta-Analysis

Background Systemic inammatory response (SIR) plays important roles in initiation, promotion and progression of tumor. However, the prognostic role of baseline circulating platelet–to–lymphocyte ratio (PLR) (known as a marker of SIR) in human stage (cid:0) gastric cancer (GC) remains controversial. Hence, we performed this meta-analysis to assess the value of it in prognosis prediction for stage (cid:0) GC patients. Methods We searched PubMed, Embase and EBSCO to identify the studies and computed extracted data with STATA 12.0. Results A total of 2721 patients with stage (cid:0) GC from 12 published studies were incorporated into this meta-analysis. We found that elevated baseline circulating PLR was signicantly associated with decreased overall survival (OS), but not with progression–free survival (PFS) in stage (cid:0) GC patients. However, in stratied analyses, high PLR was remarkably associated with worse 1-year OS, but not with 2-year, 3-year, 4-year or 5-year OS; In addition, it was considerably related with reduced 6-month PFS, but not with 1-year or 2-year PFS. Moreover, high PLR markedly correlated with peritoneal metastasis of patients. elevated baseline is valuable index for these patients modifying the inammatory responses may have a potential for effective treatment.


Introduction
Human gastric cancer (GC) is one of the most common fatal malignancies worldwide. Although progress in early diagnosis and therapeutic strategies have bene ted these patients, the advance in prognosis prediction especially in stage GC still remains poor. Recently, several systemic in ammatory response (SIR) -related hematological factors have been extensively investigated to risk-stratify cancer patients to improve treatment selection and to predict survival in many types of cancers including stage GC.
The platelet-to-lymphocyte ratio (PLR), known as a marker of the SIR, which can easily be measured on the basis of absolute platelets and lymphocytes in the clinical setting, has been regarded as a potential prognostic index in various cancers [1]. Previous studies have reported that circulating PLR was remarkably associated with clinical outcomes of GC patients [2,3]. However, different stages indicate very differential survival of cancer; and SIR will also vary as tumor progresses. They haven't clari ed the association between such index and prognosis in stage GC patients in those studies. Although many researchers have investigated the value of baseline circulating PLR in prognosis prediction for stage GC patients, their results were not consistent even controversial [4][5][6]. A re-assessment is therefore warranted. Moreover, the potential of PLR in peripheral blood before treatment as an effective prognostic index and therapeutic strategy is necessary to be explored.
In this study, we performed the meta-analysis to quantitatively summarize the association between baseline circulating PLR and clinical outcomes such as overall survival (OS) and progression-free survival (PFS) in stage GC patients, and discovered that elevated baseline circulating PLR was signi cantly associated with decreased 1-year OS and 6-month PFS, but not with 2-year, 3-year, 4-year or 5-year OS, and 1-year or 2-year PFS in stage GC patients. Thus, baseline circulating PLR may be a prognostic index for these patients.

Search strategy
We searched PubMed, Embase and EBSCO for studies assessing the PLR in peripheral blood before treatment and survival in stage GC patients from 1996 to March 31th 2021. The keywords adopted for search were ("platelet to lymphocyte ratio" OR "PLR" OR "in ammation") AND ("gastric cancer" OR "stomach cancer") AND ("prognosis" OR "survival"). A total of 524, 836 and 1748 entries were identi ed in PubMed, Embase and EBSCO respectively.

Inclusion and exclusion criteria
Inclusion criteria of the meta-analysis were: studies must have (1) been published as original articles in English; (2) assessed human subjects with histopathologically diagnosed with stage GC; (3) provided hazard ratios (HRs) with 95% con dence interval (CI), or Kaplan -Meier curves of high and low circulating PLR before treatment with OS or PFS.
The exclusion criteria were that studies have not been published as research articles or full texts including commentary, case report and letters to editors and conference abstracts; Studies without su cient data for hazard ratios (HRs) evaluation; studies that detected PLR not in peripheral blood or after treatment or not in stage disease.

Endpoints
In this meta-analysis, we recorded OS as the primary endpoint; while PFS were regarded as the second endpoint. Individual studies de ned cut-offs of PLR and classi ed patients into high-and low-groups.

Data extraction
Two authors (GM.H. and SM.W.) independently reviewed and extracted information including rst author's name, publication year, number of patients, median age, time of follow-up and cut-off value to determine high PLR. OS, PFS and clinicopathological data including tumor differentiation, peritoneal, liver or lung metastasis etc were extracted from the text or tables.

Quality assessment
Two independent authors adopted Newcastle-Ottawa Scale (NOS) [7] to assess the quality of individual study, and achieved consensus for each item under the help of the third or more authors. Six or above that the study scored was regarded as high quality.

Statistical Analysis
Relevant data were combined into hazard ratios (HRs) for OS, PFS, and odds ratios (ORs) for clinicopathological features such as tumor differentiation, peritoneal metastasis etc with STATA 12.0 respectively based on the random-effect model if statistical heterogeneity was considerable[8] otherwise, the xed -effect model was applied [9]. We also adopted sensitivity analysis, Begg's funnel plot and Egger's test [10] to determine the in uence of individual study on the overall result and potential publication bias respectively. All P values were two-sided and below 0.05 was treated as statistical signi cance.

Search results and description of studies
Flow chart diagram of study selection was exhibited in Fig. S1. Twelve studies with 2721 patients were ultimately included in this meta-analysis [4][5][6][11][12][13][14][15][16][17][18][19]. And all these studies were scored 6 or above after careful assessment with the Newcastle-Ottawa Scale (NOS). Characteristics of researches being appropriate for data integration were exhibited in Table 1 and Table S1.

Clinicopathological features
We next investigated whether high baseline circulating PLR correlated with clinicopathological features, and discovered that it was considerably associated with peritoneal metastasis (OR = 1.30, 95% CI 1.04 to 1.63, P = 0.024), but not with liver (OR = 1.41, 95% CI 0.84 to 2.39, P = 0.195) or lung (OR = 1.03, 95% CI 0.35 to 3.04, P = 0.954) metastasis in stage disease. (Fig. S2A, B and C) And there was no correlation between PLR and tumor differentiation (OR = 1.10, 95% CI 0.82 to 1.47, P = 0.528) of patients. (Fig. S2D) Sensitivity analysis Sensitivity analysis demonstrated that each included research had no impact on the overall result for OS or PFS. (Fig. S3) Publication bias Funnel plot and Egger's test indicated that no signi cant publication bias existed between combined therapy and OS (P = 0.348) or PFS (P = 0.715) in patients. (Fig. S4)

Discussion
Systemic in ammatory response is closely related to the initiation, promotion and progression of cancer. [20] In this study, we found that high baseline circulating PLR remarkably decreased OS in stage GC patients; However, we noted that it didn't reduce PFS in these patients. In strati ed analyses, high PLR was remarkably associated with worse 1-year OS and 6-month PFS, but not with 2-year, 3-year, 4-year or 5-year OS, or 1-year, 2year PFS. In addition, high PLR was considerably correlated with peritoneal metastasis of GC. These ndings suggested that high baseline circulating PLR played a critical role in promoting tumor progression and metastasis of GC.
Several potential mechanisms might be responsible for the close association between increased PLR and worse prognosis. Previous researches have demonstrated that platelets play a key role in tumor progression and are associated with poor survival in patients with various types of malignancies [21]. Platelets can induce angiogenesis via the secretion of vascular endothelial growth factor (VEGF) and inhibit anti-tumor response mediated by effector T cells [22]. Platelets can also protect the circulating tumor cells (CTCs) from shearing stresses during circulation [23]. Lymphocytes have an important role in cancer immune surveillance and prevent development of malignancy [24]. The decrease in CD4+ T-helper cells may lead to a suboptimal lymphocyte-mediated immune response to cancer cells [25]. Taken together, we observed that an increase in the platelet count or decrease in the lymphocyte count in the peripheral blood correlate with tumor initiation and progression. Hence, the PLR may help to predict prognosis and re ect the degree of tumor progression in stage GC. However, in this study, we noted that pre-treatment PLR only correlated with worse 1-year OS and 6-month PFS rather than 2-year, 3-year, 4-year or 5-year OS, or 1-year, 2-year PFS. The mechanism underlying such results needs further investigation.
There is a limitation that should be noted from this meta-analysis, studies with negative results might not be published, which could cause potential publication bias.
In conclusion, elevated circulating PLR before treatment leads to worse 1-year OS and 6-month PFS in stage GC patients, implicating that it might be a valuable prognostic index and modifying the in ammatory responses may have a potential for effective treatment for these patients.

Declarations
Ethics approval and consent to participate The ethical approval was unnecessary because this study based on summary and analysis of the results of previous studies.

Consent for publication
Not applicable.

Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.

Competing interests
The authors have declared that no competing interests exist. Forest plots describing HR of the association between elevated baseline circulating PLR and OS in stage GC patients. HR: hazard ratio; GC: gastric cancer; OS: overall survival.

Figure 3
Forest plots describing HRs of the association between elevated baseline circulating PLR and PFS in stage GC patients. HR: hazard ratio; GC: gastric cancer; PFS, progression-free survival.