Abstract
Background
The prognostic and clinicopathological significance of the platelet to lymphocyte ratio (PLR) has been studied in various cancers. However, studies examining the role of PLR in esophageal cancer have not yielded consistent results. The purpose of this meta-analysis was to study the prognostic and clinicopathological significance of PLR in esophageal cancer patients.
Methods
We performed a literature search in three major databases: PubMed, Web of Science and Embase (up until May 1, 2017). The clinicopathologic significance of PLR and its prognostic significance were analyzed.
Results
Our meta-analysis consisted of 13 studies with 4,621 patients. The pooled hazard ratios (HRs) showed that a high PLR was associated with poor survival of esophageal cancer [HR =1.283; 95% confidence interval (CI): 1.173–1.404; P<0.001]. Subgroup analysis revealed that elevated PLR was associated with poor survival in esophageal squamous cell carcinoma (HR =1.281; 95% CI: 1.098–1.493; P=0.002). The pooled odds ratio (OR) indicated that high PLR was also associated with the depth of tumor invasion (OR =1.543, 95% CI: 1.269–1.876, P<0.001), lymph node metastasis (OR =1.427, 95% CI: 1.195–1.705, P<0.001), tumor length (OR =1.81, 95% CI: 1.331–2.461, P<0.001), and Tumor stage (OR =1.459, 95% CI: 1.235–1.724, P<0.001).
Conclusions
Our results demonstrate that elevated PLR was significantly associated with poor prognosis of esophageal cancer. Furthermore, the high PLR might predict worse clinicopathological features of esophageal cancer patients.
Keywords: Meta-analysis, esophageal neoplasms, platelet to lymphocyte ratio (PLR), prognosis
Introduction
Esophageal cancer is one of the most common cancer types worldwide with a poor prognosis. Although multimodal therapeutic strategies have been used to treat esophageal cancer, including radical operation, chemotherapy, and radiotherapy, the 5-year survival rate remains low (1-3). The identification of prognostic factors in esophageal cancer is thus urgently required to better treat this disease.
Previous studies have established a close relationship between inflammation and cancer (4). Chronic inflammation can induce the development of various types of cancers, and the microenvironment caused by inflammation or by the oncogenic changes during tumorigenesis may promote cancer angiogenesis and metastasis (4,5). Some inflammatory factors in the blood, such as lymphocytes, neutrophils, monocytes and platelets, show alterations in cancer (6-8). Many inflammatory factors have been associated with prognosis in various cancers. The combination of inflammatory factors, such as platelet-to-lymphocyte ratio (PLR), was also reported to be a prognostic factor in many cancers such as breast, lung and gastric cancers (9-12).
Recent studies have shown that a high PLR might be associated with poor prognosis of esophageal cancer (13,14). However, this result was not confirmed in other studies (15,16). In addition, several inflammatory factors may affect tumor characteristics, such as tumor length and depth of tumor invasion. We performed this meta-analysis to examine the potential role of PLR in the prognosis of esophageal cancer and its relationship with tumor pathological characteristics.
Methods
Search strategy
We performed a literature search in the PubMed, Embase, and Web of Science databases (up until May 1, 2017). We used the following search terms: prognosis (e.g., “prognoses”, “prognostic”, “survival”), PLR (e.g., “platelet lymphocyte ratio”, “platelet to lymphocyte ratio”, “platelet-to-lymphocyte ratio”), and esophageal cancer (e.g., “esophageal neoplasm”, “esophageal cancer”, “esophageal carcinoma”) (details seen in Supplementary).
Selection criteria
We used the following criteria for inclusion: the diagnosis for esophageal cancer was proven by pathology, and the correlation between pretreatment PLR and overall survival (OS) was studied. The exclusion criteria were as follows: article types of reviews, letters, abstracts, and case reports; studies written in a language other than English; absence of hazard ratio (HR) and 95% confidence interval (CI) values; and studies without a cutoff value of PLR.
Data extraction and quality assessment
Two researchers (Deng JH and Sun Y) independently extracted data from relevant studies. In cases of disagreements, another researcher (Zhang P) was consulted. The following information was collected: authors’ names, year of publication (we included the final published year), study country, study design, gender, age, stage of disease, pathological type, cutoff values for PLR, HR with 95% CI of PLR for OS, type of study, treatment intent, treatment strategy and survival data. We used the Newcastle-Ottawa Scale (NOS) for quality assessment of the included research (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). If the NOS score was ≥6 points, we considered the article was high quality
Statistical analysis
Meta-analysis was performed using Stata 12.0 software (STATA, College Station, TX, USA). HRs for the association of PLR and esophageal cancer were obtained from the research. When HRs was reported in both univariate and multivariate analyses, we used the multivariate-adjusted HRs. The pooled HRs was finally summarized from each study of HRs and their 95% CI. The I-squared (I2) statistic was used to evaluate the heterogeneity of the studies. If I2 >50%, meta-analysis was chosen to evaluate with a random effects model; otherwise, the fixed effect model was chosen. Odds ratios (ORs) were used to estimate the association between PLR and clinicopathological characteristics. We estimated publication bias by Begg’s funnel plot test and Egger’s linear regression test. We also used country, cutoff, patient’s number (simple size), treatment strategy and pathologic type for subgroup analysis.
Results
Study Characteristics
A total of 59 studies were initially identified after searching the databases. After browsing the title and abstracts, 34 studies were excluded. We then reviewed the remaining 25 studies and excluded 12 studies for the following reasons: two studies used data with a continuous PLR level for survival analysis, without a clear cutoff value; one study performed the analysis in the samples with a repeated population; four studies did not use OS as an endpoint; two studies did not describe the relationship between PLR and OS; and three studies did not report the HR value. A final 13 studies were included in the meta-analysis, with 4,621 patients (Figure 1) (13-25). These studies were published from 2013 to 2017. The most common type of pathology involved in these studies was esophageal squamous carcinoma (ESCC). The PLR cutoff point ranged from 117.07 to 244. The detailed information of these studies is shown in Table 1. NOS scores of all the studies were at least 6 or more.
Figure 1.
The flow diagram for selection of studies. PLR, platelet to lymphocyte ratio; OS, overall survival; HR, hazard ratio.
Table 1. Characteristics of all eligible studies.
| Study | Year | Country | No. (male/female) | Age (mean or median) | Treatment | Intent | Stage | Cutoff value | Median OS (m) (low/high PLR) | HR (M/U) | Result | Histology | Study type |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Feng et al. | 2013 | China | 43 (30/13) | 58.7±7.8 | Mix | Cur | I–III | 150 | NR | M | Positive | Small cell | Uni/Re |
| Feng et al. | 2014 | China | 483 (411/72) | 59.1±8.0 | S | Cur | I–III | 150 | NR | M/U | Positive | SCC | Uni/Re |
| Han et al. | 2015 | China | 218 (177/41) | 60.5 | Mix | Cur | I–III | 244 | 40/29.9 | M/U | Negative | SCC | Uni/Re |
| Xu et al. | 2015 | China | 468 (416/52) | 58 | Mix | Cur | I–III | 147 | NR | U | Negative | SCC | Uni/Re |
| He et al. | 2015 | China | 820 (526/294) | 60.0±9.3 | S or NR | NR | I–IV | 194 | NR | M | Negative | SCC + others | Uni/Re |
| Messager et al. | 2015 | UK | 153 (128/25) | 64.9 | Mix | Cur | I–III | 192 | NR | M/U | Positive | ADC | Uni/Re |
| Geng et al. | 2016 | China | 916 (696/220) | 60 | S | Cur | I–III | 120 | 53/36 | M/U | Negative | SCC | Uni/Re |
| Ji et al. | 2016 | China | 41 (38/3) | 56.6±7.2 | Mix | Cur | I–III | 130 | NR | U | Positive | SCC | Uni/Re |
| Sun et al. | 2016 | China | 362 (268/94) | 58 | Mix | Cur | I–III | 150 | NR | U | Negative | SCC | Uni/Re |
| Toyokawa et al. | 2016 | Japan | 185 (152/33) | 64 | Mix | Cur | I–IV | 193 | NR | M | Negative | SCC | Uni/Re |
| Zhang et al. | 2016 | China | 468 (376/92) | 59.5±9 | Mix | Cur | I–III | 117.07 | NR | M/U | Negative | SCC | Uni/Re |
| He et al. | 2017 | China | 317 (268/49) | 60 | Mix | Cur | I–IV | 150 | 44/22.1 | M | Positive | SCC | Uni/Re |
| Hirahara et al. | 2017 | Japan | 147 (132/15) | NR | S | Cur | I–III | 147 | NR | U | Negative | SCC | Uni/Re |
No., patient number; M, hazard ratio from multivariate analysis; U, HR from univariate analysis; Mix, mixed treatment, combing different treatment methods (such as surgery, radiotherapy, chemoradiotherapy or chemotherapy); S, surgery; NR, not reported; HR, hazard ratio; Intent, treatment intent; Cur, curative intent; OS, overall survival; SCC, squamous cell carcinoma; ADC, adenocarcinoma; Uni, Uni-centric; Re, retrospective.
The role of PLR in the prognosis of esophageal cancer
All 13 studies retrospectively reported the relationship between PLR and OS. We found that a high PLR was positively related to poor OS (pooled HR =1.283, 95% CI: 1.173–1.404; P<0.001, Figure 2). We used the fixed-effect model, for no obvious heterogeneity existed (I2 =49.4%, Ph=0.022). First we performed subgroup analysis with the pathologic type. We found that 10 studies reported the association between PLR and OS in ESCC and demonstrated that a high PLR was related to poor OS (HR =1.281, 95% CI: 1.098–1.493, P=0.002) of ESCC (Figure 3); here we used random effect model for I2 >50%. We also performed subgroup analysis by cutoff value, sample size and countries. Subgroup analysis by cutoff values showed an HR for cutoff value ≥150 of 1.413 (95% CI: 1.136–1.758, P=0.002, I2 =56.1%, Ph=0.026) and for cutoff value <150 of 1.187 (95% CI: 1.05–1.341; P=0.006; I2 =7.4%, Ph=0.365). In patients treated with surgery alone, the combined HR was 1.407 (95% CI: 1.018–1.945; P=0.039; I2 =73.2%, Ph=0.024); for research with multimodal treatment, the HR was 1.255 (95% CI: 1.102–1.43; P=0.001; I2 =48.6%, Ph=0.049) (Table 2). Subgroup analyses by sample size and countries are shown in Table 2.
Figure 2.
Forest plot of meta-analysis between PLR and OS in esophageal cancer. PLR, platelet to lymphocyte ratio; OS, overall survival; HR, hazard ratio; CI, confidence interval; ES, effect size.
Figure 3.
Forest plot of meta-analysis between PLR and OS in ESCC. PLR, platelet to lymphocyte ratio; OS, overall survival; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; CI, confidence interval; ES, effect size.
Table 2. Meta-analysis results of PLR in esophageal cancer prognosis.
| Factor | No. of study | No. of patients | Effect model | HR (95% CI) | P value | Heterogeneity | |
|---|---|---|---|---|---|---|---|
| I2 (%) | Ph | ||||||
| OS | |||||||
| Overall | 13 | 4,621 | Fix | 1.283 (1.173, 1.404) | 0.000 | 49.4 | 0.022 |
| Random | 1.321 (1.146, 1.523) | 0.000 | |||||
| Country | |||||||
| China | 10 | 4,136 | Fix | 1.271 (1.158, 1.396) | 0.000 | 55.8 | 0.016 |
| Random | 1.300 (1.113, 1.520) | 0.001 | |||||
| Japan | 2 | 332 | Fix | 1.243 (0.852, 1.814) | 0.260 | 0.0 | 0.907 |
| Random | 1.243 (0.852, 1.814) | 0.260 | |||||
| Treatment | |||||||
| Surgery | 3 | 1,546 | Fix | 1.339 (1.164, 1.540) | 0.000 | 73.2 | 0.024 |
| Random | 1.407 (1.018, 1.945) | 0.039 | |||||
| Mix | 9 | 2,255 | Fix | 1.255 (1.102, 1.430) | 0.001 | 48.6 | 0.049 |
| Random | 1.317 (1.073, 1.615) | 0.008 | |||||
| Cutoff value | |||||||
| ≥150 | 8 | 2,581 | Fix | 1.407 (1.233, 1.606) | 0.000 | 56.1 | 0.026 |
| Random | 1.413 (1.136, 1.758) | 0.002 | |||||
| <150 | 5 | 2,040 | Fix | 1.187 (1.050, 1.341) | 0.006 | 7.4 | 0.365 |
| Random | 1.189 (1.042, 1.356) | 0.010 | |||||
| Sample size | |||||||
| ≥300 | 7 | 3,834 | Fix | 1.261 (1.147, 1.388) | 0.000 | 56.9 | 0.031 |
| Random | 1.273 (1.095, 1.479) | 0.002 | |||||
| <300 | 6 | 787 | Fix | 1.461 (1.124, 1.908) | 0.005 | 42.5 | 0.122 |
| Random | 1.564 (1.085, 2.254) | 0.016 | |||||
| Pathologic type | |||||||
| ESCC | 10 | 3,605 | Fix | 1.267 (1.150, 1.396) | 0.000 | 50.4 | 0.034 |
| Random | 1.281 (1.098, 1.493) | 0.002 | |||||
| Other types* | 3 | 1,016 | 1.386 (1.093, 1.759) | 0.007 | 60.7 | 0.078 | |
| 1.717 (1.014, 2.906) | 0.044 | ||||||
*, the article included other pathologic types except squamous cell carcinoma or with a mixed type. OS, overall survival; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; CI, confidence interval; Mix, mixed treatment, combing different treatment methods, including surgery, radiotherapy, chemoradiotherapy or chemotherapy.
PLR and clinicopathological features
The association between PLR and clinicopathological characteristic features was studied in several articles (13-15,18,21-25). Six studies reported the association of PLR with depth of tumor invasion in esophageal cancer. The combined OR revealed that a high PLR was related to a deeper tumor invasion (OR =1.543, 95% CI: 1.269–1.876, P<0.001). Seven studies reported that a high PLR was positively associated with lymph node metastasis of esophageal cancer (OR =1.427, 95% CI: 1.195–1.705, P<0.001). Furthermore, a high PLR was positively associated a longer tumor length (OR =1.810; 95% CI: 1.331–2.461, P<0.001) and a higher TNM stage (OR =1.459, 95% CI: 1.235–1.724, P<0.001). The level of PLR was not related to other clinicopathological factors (tumor differentiation OR =1.196, 95% CI: 0.978–1.462; P=0.081; vascular invasion OR =1.104, 95% CI: 0.709–1.717, P=0.663) (Table 3).
Table 3. Relationship between PLR and the clinicopathologic features.
| Variable | No. of studies | No. of patients | Effect of model | OR (95% CI) | P value | Heterogeneity | Egger’s P value | |
|---|---|---|---|---|---|---|---|---|
| I2 (%) | Ph | |||||||
| Tumor invasion (T3/4 vs. T1/2) | 6 | 1,848 | Fixed | 1.543 (1.269, 1.876) | 0.000 | 0.0 | 0.629 | 0.022 |
| Random | 1.543 (1.269, 1.876) | 0.000 | ||||||
| Lymph node metastasis (yes vs. no) | 7 | 2,165 | Fixed | 1.427 (1.195, 1.705) | 0.000 | 17.9 | 0.294 | 0.341 |
| Random | 1.461 (1.175, 1.816) | 0.001 | ||||||
| Differentiation (poor vs. well/moderate) | 6 | 2,128 | Fixed | 1.196 (0.978, 1.462) | 0.081 | 0.0 | 0.477 | 0.677 |
| Random | 1.196 (0.978, 1.462) | 0.081 | ||||||
| Vascular invasion(yes vs. no) | 3 | 567 | Fixed | 1.104 (0.709, 1.717) | 0.663 | 0.0 | 0.961 | 0.749 |
| Random | 1.104 (0.709, 1.717) | 0.663 | ||||||
| TNM stage(stage III/IV vs. I/II)) | 7 | 2,612 | Fixed | 1.459 (1.235, 1.724) | 0.000 | 29.6 | 0.202 | 0.345 |
| Random | 1.504 (1.198, 1.889) | |||||||
| Tumor length (>3 vs. ≤3 cm) | 4 | 1,061 | Fixed | 1.810 (1.331, 2.461) | 0.000 | 12.3 | 0.331 | 0.607 |
| Random | 1.774 (1.255, 2.507) | 0.001 | ||||||
Ph, P value for heterogeneity; No., number; OR, odds ratio; CI, confidence interval; TNM, tumor node metastasis; T, depth of tumor invasion.
Publication bias
Egger’s and Begg’s test was used evaluate publication bias. No publication bias was detected (P=0.126 and P=0.127 for Egger’s and Begg’s tests, respectively; Figure 4).
Figure 4.
Funnel plot for the publication bias of HR for OS. LNHR, natural logarithm hazard ratio; SELNHR, standard error of natural logarithm hazard ratio; HR, hazard ratio; OS, overall survival.
Discussion
Inflammation plays an important role in the development of cancer. The cells and mediators of inflammation create a specific microenvironment, which influences tumor growth, progression, angiogenesis and metastasis (26). Systematic inflammatory response is a highlight in various research studies, and current interest is focused on the prevention and treatment of cancer by addressing abnormal inflammation (27).
Platelets play an important role in immune and inflammation responses and participate in cancer invasion and metastasis (28). Many platelet-associated chemokines can modulate inflammation within the tumor environment and tumor angiogenesis, such as platelet factor 4 (PF-4/CXCL4) and connective tissue activating peptide III (CTAP-III) (29). Lymphocytes have been shown to exert an important role in the cancer immunosurveillance process. Shankaran et al. reported that lymphocytes and IFN-gamma collaborate to protect against the development of chemically-induced sarcomas and spontaneous epithelia carcinomas (30). Inflammation plays an important role in the development of esophageal cancer. Chronic inflammation triggered by environmental exposures may activate the proinflammatory signaling pathway, which promotes the proliferation and survival of cancer cells (31).
The levels of platelets and lymphocytes are altered in the blood of cancer patients (7,8,32,33). Furthermore, the prognostic role of a combination of blood platelets and lymphocytes has been reported in various solid tumors (10,11). Evaluation of the PLR is easy to perform in most patients. Some studies have shown that a high PLR might be associated with the poor prognosis of esophageal cancer, but this association has not been completely confirmed. Therefore, we performed this meta-analysis to confirm the role of PLR in esophageal cancer.
In this meta-analysis, we found that a high PLR predicts poor prognosis in esophageal cancer. We then performed a subgroup analysis and also determined a prognostic role of PLR in ESCC, the major histological type. We also analyzed the relationship between PLR and clinicopathologic features. The result indicated that the elevated PLR level was associated with deeper tumor invasion, lymph node metastasis, longer tumor length and higher tumor stage. Taken together, these data suggest that the level of PLR is important for predicting the prognosis and the status of clinicopathologic features. As well known, the PLR is easily measured in the clinical setting because each patient undergoes a blood test before treatment and the cost is low. Thus, PLR might be a useful and convenient tool for clinicians when performing clinical treatment and evaluating the outcomes.
One previous study performed a meta-analysis to investigate the prognostic significance of PLR in esophageal cancer (34). In this previous study, the authors found that high PLR was significantly predictive of poorer OS, deeper tumor invasion, and lymph node metastasis. However, they only included four studies. They did not perform a subgroup analysis according to the pathological types. In the present study, we evaluated a much larger group, including 4,621 patients from 13 studies. We demonstrated for the first time the prognostic role of PLR in ESCC. Furthermore, we concluded that more clinical features might be associated with PLR, such as tumor length and tumor stage.
Our study had several limitations. First, most of the studies were performed in Asian countries (China and Japan), and only one study was performed in a Western country. We did find some studies published in Western countries (35,36), but they did not meet the study criteria. Therefore, our preliminary findings need to be confirmed in other regions. Second, the most prevalent histological type was ESCC. However, different subtypes of esophageal cancer show different biological behaviors and prognoses. Our study did not include enough data on esophageal adenocarcinoma and small cell carcinoma. Only one article in our meta-analysis definitely studied the relationship between esophageal adenocarcinoma and PLR. The researchers found that high PLR is associated with poor OS and disease-free survival (DFS) for esophageal and junction adenocarcinoma (13). This is a positive result but needs further study to prove the result. We should also take this result in caution. Most tumors in their study were located in the esophagus, but a small part of the carcinoma was located in the gastro-esophageal junction, close to the esophagus, often studied, and treated with esophageal tumor (2). In another article, 80% of the patients were diagnosed as having adenocarcinoma (37). In their study, they found that elevated PLR might be predictive of worse OS in esophageal cancer. However, it was excluded in our meta-analysis for using data without a clear cutoff value for analysis. Therefore, more studies are needed to confirm the role of PLR in other pathological subtypes.
Conclusions
Our meta-analysis confirmed that a high PLR was associated with poor prognosis of esophageal cancer, especially in ESCC. Furthermore, the PLR level is related to clinicopathologic features of esophageal cancer. More studies are required in other histologic types and geographic regions. More effort is required to predict prognosis of esophageal cancer patients more accurately and develop novel treatment strategies, including anti-inflammatory therapy.
Embase strategy.
| Search date | Combine | Results |
|---|---|---|
| May 2017 | #20. #17 AND #18 AND #19 | 37 |
| #19. #13 OR #14 OR #15 OR #16 | 3,004 | |
| #19. #13 OR #14 OR #15 OR #16 | 64,034 | |
| #17. #1 OR #2 OR #3 OR #4 OR #5 OR #6 | 3,512,600 | |
| #16. ‘plr’ | 2,678 | |
| #15. ‘platelet-to-lymphocyte ratio’ | 766 | |
| #14. ‘platelet to lymphocyte ratio’ | 766 | |
| #13. ‘platelet lymphocyte ratio’/exp | 1,245 | |
| #12. ‘esophagus carcinoma’ | 15,242 | |
| #11. ‘esophageal carcinoma’ | 7,771 | |
| #10. ‘esophageal cancer’ | 24,793 | |
| #9. ‘esophagus neoplasm’ | 17 | |
| #8. ‘esophageal neoplasm’ | 421 | |
| #7. ‘esophagus cancer’/exp | 57,252 | |
| #6. ‘mortality’ | 1,073,552 | |
| #5. ‘survival’ | 1,391,365 | |
| #4. ‘outcome’ | 2,054,741 | |
| #3. ‘prognostic’ | 359,252 | |
| #2. ‘prognoses’ | 9,581 | |
| #1. ‘prognosis’/exp | 605,644 |
Web of science.
| Search format | Results | Combine |
|---|---|---|
| #4 | 50 | #3 AND #2 AND #1 |
| Index=SCI-EXPANDED, SSCI time span=1992-2017 | ||
| #3 | 2,777 | Term: (platelet lymphocyte ratio) OR term: (platelet to lymphocyte ratio) OR term: (platelet-to-lymphocyte ratio) OR term: (PLR) |
| Index=SCI-EXPANDED, SSCI time span=all years | ||
| #2 | 42,988 | Term: (Esophageal Neoplasm) OR term: (Esophagus Neoplasm) OR term: (Esophagus Cancer) OR term: (Esophageal Cancer) OR term: (esophageal carcinoma) OR term: (Esophagus carcinoma) |
| Index=SCI-EXPANDED, SSCI time span=all years | ||
| #1 | 2,864,518 | Term: (Prognosis) OR term: (Prognoses) OR term: (prognostic) OR term: (outcome) OR term: (survival) OR term: (mortality) |
| Index=SCI-EXPANDED, SSCI time span=all years |
Acknowledgements
We thank Dr. Xiang Wang for statistic assistance.
Funding: This work was supported by a grant from a research fund of Wuhan Tongji Hospital [2015].
Footnotes
Conflicts of Interest: The authors have no conflicts of interest to declare.
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