The current meta-analysis was designed to investigate the prognostic value of elevated PLR for DFS and OS in GC patients. Pooled results demonstrated that elevated PLR was associated with poor OS and DFS. Moreover, elevated PLR was correlated with lymph node metastasis, serosal invasion and advanced TNM stage with GC.
Despite the development of new surgical techniques and the use of chemotherapy and radiotherapy, gastric cancer still remains one of the main causes of cancer-related mortality and morbidity worldwide . Because individual GC patients present with different conditions, including different degrees of invasion, differentiation and TNM stages, the survival outcomes may vary. Therefore, identification of more prognostic factors and different risk groups would contribute to the optimization of individualize treatment. It is important to identify a reliable biomarker, which is simple, low-cost, and effective, to predict the prognosis of patients with gastric cancer.
In recent years, the studies about the relationship between the inflammation and tumor have been developed. Inflammatory cells are critical factors in the tumor cell micro-environment and important for repair of tissue damage [52-54]. The inflammation results are involved in lymphocytopenia, neutrophilia, thrombocytosis and leukocytosis [55, 56]. The tumor-generated inflammatory reaction may contribute to tumor growth, progression and metastasis through several mechanisms, including the up-regulation of inflammatory mediators and cytokine, aberrant activation of immune regulatory cytokines, suppression of apoptosis, and DNA damage . Recently, emerging evidence indicates that inflammatory reaction is an important factor for the initiation, progression and prognosis of numerous cancers, such as GC [57, 58]. Helicobacter pylori infection in GC is characterized by an inflammatory infiltrate, consisting mainly of neutrophils and T cells . Moreover, circulating lymphocytes were reported that could reflect patient’s inflammatory status . Thus, some inflammation-based parameters, such as lymphocyte count, systemic immune-inflammation index (SII), platelet–lymphocyte ratio (PLR), and neutrophil–lymphocyte ratio (NLR), have been used to predict survival and recurrence in cancer patients [44, 61-64].
The PLR, which combines platelet and lymphocyte counts, is a representative index of systemic inflammation and immune status [65, 66]. Accumulating evidence indicates the correlation of PLR with different stages of tumor development, chemotherapeutic response and prognostic survival outcomes of GC patients [38, 42, 66]. The specific mechanisms involved are complex and remains unclear. One potential explanation is that a decreased PLR may reflect four disadvantages including an inflammatory status, immune disorders, malnutrition and a tendency for micro-vessel thrombosis [39, 67]. Lymphocytes have an important role in cancer immune surveillance and prevent development of malignancy . A pro-inflammatory status leads to compromised cell-mediated immunity and an impaired T-lymphocytic response via cytokines . The decrease in CD4+ T-helper lymphocytes may result in a suboptimal lymphocyte mediated immune response to tumor cells . The T-lymphocytic cell-mediated malnutrition is a major cause of delayed wound healing [71, 72]. Platelet count is an additional index of a systemic inflammatory response and potential micro-vessel thrombosis, which could inhibits wound healing via the deterioration of blood circulation in tissues [11, 65, 73]. Otherwise, Aggregated platelets can promote tumor growth via releasing pro-angiogenic mediators within the micro-vasculature of tumors . Platelets also inhibit tumor cell extravasation by potentiating tumor-cell-induced endothelial cell retraction, and enhance tumor cell adhesion and spreading across the extracellular matrix, which contribute to the promotion of tumor cell proliferation and metastasis . Therefore, lymphocytopenia and thrombocytosis are considered as negative prognostic markers in various cancers [76-79]. However, a decreased lymphocyte count or an increased platelet count alone may not reflect the host systemic inflammatory response and tumorigenesis process. Thus, the PLR, which combines platelet and lymphocyte counts, may reflect the bonding prognostic information of these two processes, which could be a stronger predictor of outcome in GC than platelet or lymphocyte count alone. In addition, the value of PLR could be acquired from the routine laboratory tests, which provides clinical implications at a low cost.
Accumulated studies have assessed the association between PLR and the diagnosis and prognosis of gastric cancer. Some studies showed that elevated PLR predicted poor OS and DFS in GC patients after surgery [22, 24]. However, some other studies did not detect the significant prognostic value of PLR for GC patients [7, 47]. Lian et al. reported that low PLR levels correlated with better clinicopathological features, including decreased depth of invasion, less lymph node metastasis and early tumor stage . Recently, a meta-analysis containing 8 studies comprising 4,513 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 [82-86]. 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 PLR might have powerful prognostic efficiency for poor OS in GC and could predict shorter DFS in GC. What’s more, subgroup analyses for OS revealed the similar result in Asian populations, but not in Caucasian populations. Moreover, we also eliminated the effect of different treatment methods on the prognostic value of the PLR. Our results showed that elevated PLR significantly predicted shorter OS in patients receiving surgery treatment, but did not have prognostic efficiency for patients receiving chemotherapy or mixed treatment. Except for the reason of too few studies included, another possible major reason is that the patients in the chemotherapy or mixed groups have huge differences in medical conditions and disease status, resulting in inability to obtain significant results. To evaluate the effect of different cut-off values on the prognostic value of PLR in GC patients, subgroup analyses showed that patients with elevated PLR suffered worse OS than those with low PLR, regardless of the different cut-off values. The same effects were indicated in the subgroup analyses by different sample size of patients. These results might strengthen the possibility that PLR could act as a reliable prognostic biomarker in GC.
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.