Prognostic value of pretreatment platelet counts in lung cancer: a systematic review and meta-analysis.

Background The prognostic value of elevated pretreatment platelet counts remains controversial in lung cancer patients. We performed the present meta-analysis to determine its precise role in these patients. Methods We employed a multiple search strategy in the PubMed, EMBASE and Cochrane Library databases to identify eligible studies. Disease-free survival (DFS)/progression-free survival (PFS)/time to progression (TTP) and overall survival (OS) were used as outcomes with hazard ratios (HRs) and 95% confidence intervals (CIs). Heterogeneity among the studies and publication bias were also evaluated. Results A total of 40 studies including 16,696 lung cancer patients were eligible for the analysis. Overall, the pooled analysis showed that compared with normal platelet counts, elevated pretreatment platelet counts were associated with poorer OS (HR = 1.54, 95% CI: 1.37–1.72, P < 0.001) and poorer DFS/PFS/TTP (HR = 1.62, 95% CI: 1.33–1.98, P < 0.001) in patients with lung cancer. In subgroup analyses, elevated pretreatment platelet counts were also associated with poorer OS and DFS/PFS/TTP in most subgroups. There was no evidence of publication bias. Conclusions This meta-analysis revealed that elevated pretreatment platelet counts were an independent predictor of OS and DFS/PFS/TTP in lung cancer patients. Large-scale prospective studies and a validation study are warranted.

cancer [12][13][14][15][16]. Additionally, the platelet count is convenient to perform, less expensive, and easily available. However, the current opinions about the correlation between platelet count and lung cancer prognosis are controversial. Some studies have identified that platelet count is a poor prognostic factor in NSCLC, while some suggest that platelet count has no association with lung cancer [11,[17][18][19]. Therefore, we conducted this meta-analysis to further investigate the prognostic value of pretreatment platelet counts for survival in lung cancer patients.

Search strategy
This meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Additional file 1). A comprehensive search was conducted by searching databases including the PubMed, EMBASE and Cochrane Library databases using the following terms: ("thrombocytosis" or "thrombocytosis" or "thrombocythemia" or "platelet count" or "blood platelets" or "platelets") and ("lung carcinoma" or "lung cancer" or "lung tumor" or "lung neoplasm") and ("prognosis" or "prognostic" or "survival" or "outcome") up to December 31, 2017.

Selection criteria
The inclusion criteria for this meta-analysis were as follows: (1) the diagnosis of lung cancer was confirmed pathologically; (2) platelet count was measured before treatment; (3) hazard ratios (HRs) and their 95% confidence intervals (CIs) for platelet count were reported; (4) the cut-off value of platelet count was reported; and (5) the relationship between overall survival (OS) or diseasefree survival (DFS)/progression-free survival (PFS)/time to progression (TTP) and platelet count was evaluated.

Exclusion criteria
Articles were excluded if they met the following criteria: (1) articles were reviews, case reports, letters, editorials, or conference abstracts; (2) articles that were not written in English; (3) articles missing key information for evaluating the HR and its 95% CI; (4) studies based on cancer cells or animal models and irrelevant studies; and (5) studies by the same authors with similar or overlapping data. Two reviewers assessed the candidate articles independently. Any disputes were settled through discussion.

Data extraction and quality assessment
Two reviewers independently extracted data from the selected literature and completed quality assessments. The   (Holgersson G, 2012) categorized platelet count into three groups according to cut-off values (platelet count < 150, 150 < platelet count < 350, and platelet count > 350), and there were two HRs for OS. We extracted the HR that compared the group with 150 < platelet count < 350 and the group with platelet count > 350. We used the Newcastle-Ottawa Scale (NOS) scoring system to assess the quality of the included articles [20]. Two reviewers independently evaluated the quality of each included study. The judgement criteria include three aspects of evaluation: selection, comparability, and outcome between the case group and control group. Studies with higher scores had higher quality.

Statistical analysis
The meta-analysis was conducted by STATA 12.0 software (Stata Corp, College Station, TX, USA). HRs and corresponding 95% CIs were used to analyse the association between platelet count and lung cancer. Cochrane's Q test and the I2 statistic were used to evaluate the heterogeneity among the included studies [21]. I2 > 50% or P-value< 0.05 indicated heterogeneity in the studies [22,23], and a random-effects model was adopted; otherwise, a fixedeffects model was used. Moreover, subgroup analysis was conducted to detect the potential source of heterogeneity. A P-value less than 0.05 indicated statistical significance. Publication bias was evaluated by Begg's test and Egger's regression test [24]. Additionally, sensitivity analysis was performed to check the stability of the results [25].

Study characteristics
A flow diagram demonstrating the search procedure is illustrated in Fig. 1. After the original search, 2395 records were retrieved from the electronic databases. First, we removed duplications, and 1178 records remained. Among them, another 1112 records were also excluded after examining the titles and abstracts. Next, the remaining 66 full texts were assessed for eligibility. Of these, 26 studies were excluded on account of duplicate dates and incomplete data. Ultimately, 40 studies including a total of 16,696 participants met the criteria and were enrolled in this meta-analysis [17][18][19].
The characteristics of the patients included are presented in Table 1. All included studies were published between 1976 and 2017. As shown in Table 1, 40 studies were included in the meta-analysis, 30 studies on NSCLC, 2 studies on SCLC, and 8 studies on all tumour types. Twenty-three studies were performed in Asian populations and 16 in Caucasian populations, while one study did not report the race of the participants. In terms of the cut-off value of platelet count, 8 studies used < 300 as the cut-off value, 18 studies used 300-400 as the cut-off value, one study did not report the cut-off value of platelet count, and the remaining 13 studies considered ≥400 as the cut-off value. There were 39 studies evaluating the association between OS and platelet count, while 13 studies evaluated the DFS/PFS/TTP outcome. All 40 studies reported the HR and 95% CI directly. Additionally, the quality of the studies was assessed by NOS, as shown in Table 2.

Meta-analysis OS
There were 39 studies including 16,570 patients providing data on the prognostic role of platelet count for OS in lung cancer. The results indicate that elevated platelet counts were associated with poorer OS in lung cancer patients (HR = 1.54, 95% CI: 1.37-1.72, P < 0.001, Fig. 2a). Then, we conducted subgroup analysis for further investigation, and the results are summarized in

DFS/PFS/TTP
The meta-analysis of DFS/PFS/TTP, which contained 13 studies with 7183 patients, indicated that cancer patients with high platelet counts had significantly shorter DFS/ PFS/TTP than those with low platelet counts (HR = 1.62, 95% CI: 1.33-1.98, P < 0.001, Fig. 2b). A random-effects model was used. Subgroup analysis was performed, and the results are shown in Table 3. The results suggested that in the subgroup analysis, elevated platelet count was a negative predictor in the Asian population subgroup (P < 0.001), multivariate analysis subgroup (P < 0.001), stage III-IV disease subgroup (P < 0.001), and 300 ≤ cutoff value< 400 subgroup (P < 0.001).

Publication bias and sensitivity analysis
As shown in Fig. 3, the funnel plot was symmetrical. Based on Begg's test (P = 0.866) and Egger's regression test (P = 0.376), no significant publication bias was found. Furthermore, we performed sensitivity analysis to evaluate the reliability of our results. The corresponding pooled HR values were not significantly impacted, indicating the robustness of our conclusions (Fig. 4).

Discussion
Cancer is undoubtedly one of the most serious public health problems. In the past few years, antidiuretic hormone (ADH), tumour necrosis factor alpha (TNF-α), NF-κB/p65, COX-2 and thyroid transcription factor-1 (TTF-1) have been reported to be associated with the prognosis of lung cancer. However, their specificity and sensitivity in prognosis are still not satisfactory. Therefore, the exploration of new lung cancer prognostic markers is of great significance for clinicians to take targeted measures and improve the prognosis of patients.
In recent years, it has been observed that some systemic inflammation indicators, such as the neutrophilto-lymphocyte ratio (NLR) [61], platelet-to-lymphocyte ratio (PLR) [62], Glasgow prognostic score (GPS) [63], Prognostic Index (PI) and Prognostic Nutritional Index (PNI) [64], play important roles in tumorigenesis and development and can be considered predictors of prognosis. In the 1960s, Richard B observed that the platelet count is elevated in patients with cancers compared to those with nonmalignant diseases [5]. Accumulating evidence suggests that elevated platelet counts are associated with various cancers, such as colorectal cancer, lung cancer, and endometrial carcinoma [12,65,66]. Platelets sustain proliferative signalling, resist cell death, and induce tumour angiogenesis [67]. Additionally, platelets activate the TGF-β/Smad and NF-κB pathways, further promoting tumour migration and invasion [68]. Moreover, as immune cells [69], platelets release TGF-β, reducing the expression of NKG2D and weakening the role of natural killer (NK) cells [70]. Platelets could be a prognostic predictor used in the clinic. Recently, several studies confirming the prognostic value of platelet count in lung cancer have been carried out; however, the results were inconsistent. Therefore, we conducted a meta-analysis to determine the precise role of platelet counts in lung cancer.
We combined the outcomes of 40 studies with 16,696 patients, suggesting that elevated platelet counts are a poor predictor of OS and DFS/PFS/TTP in lung cancer patients. In our subgroup analysis, elevated platelet counts were significantly associated with poor OS and DFS/PFS/TTP in diverse subgroups, such as Asian populations, tumour stages I-III, tumour stages III-IV, and studies with quality scores > 6. However, the cut-off value of the platelet count was variable. We found that elevated platelet counts were significantly associated with poor OS and DFS/PFS/TTP when the cut-off value was between 300 and 400, while the cut-off value of > 400 did not have a relationship with poor DFS/PFS/ TTP. Overall, the cut-off value of plate count between 300 and 400 can separate patients well for OS and DFS/ PFS/TTP and should be used as a prognostic biomarker in clinical use, which is more precise than the findings of the previous meta-analysis [71]. Compared to the previous meta-analysis [71], our results are more comprehensive and accurate. On the one hand, we included 40 articles in the meta-analysis, which included more new and important studies, increasing the analytical capability of the analysis. On the other hand, a more detailed subgroup analysis was performed. In addition to race and the cut-off value of platelet count, we also investigated the prognostic role of platelet count in different tumour stages, histology and quality scores. Additionally, we discussed the association between platelets and OS as well as DFS/PFS/TTP, while the previous metaanalysis studied only the significance in OS.
However, there are some limitations of this study that deserve to be mentioned. First, the studies included in our meta-analysis are retrospective studies and are therefore more likely to have selection bias. Second, although the publication bias and sensitivity analyses confirmed the credibility of our analysis, heterogeneity still existed in this meta-analysis due to several factors, such as patient characteristics, sample size, and adjuvant therapy, which were not included in our analysis. Moreover, the cut-off value for definition of the elevated platelet counts differed among the studies. Most of the studies used 300-400 as the cut-off value, while several others used < 300 or > 400 as the cut-off value of platelet count to assess the prognosis, which might lead to betweenstudy heterogeneity. Last, platelet count could be affected by several factors, such as thrombosis, hypertension, splenic diseases, blood coagulation disorders, myeloproliferative disease, infection and drugs. Therefore, platelet count cannot play a prognostic role if patients have these diseases mentioned above.

Conclusions
In conclusion, our meta-analysis revealed that elevated pretreatment platelet counts are related to poor OS and DFS/PFS/TTP in lung cancer patients and are an independent prognostic predictor of lung cancer patients. Considering the limitations, large-scale prospective studies and a validation study are warranted to confirm our results.