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Increased platelet-lymphocyte ratio closely relates to inferior clinical features and worse long-term survival in both resected and metastatic colorectal cancer: an updated systematic review and meta-analysis of 24 studies

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Oncotarget. 2017; 8:32356-32369. https://doi.org/10.18632/oncotarget.16020

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Nan Chen, Wanling Li, Kexin Huang, Wenhao Yang, Lin Huang, Tianxin Cong, Qingfang Li and Meng Qiu _

Abstract

Nan Chen1,*, Wanling Li1,*, Kexin Huang1, Wenhao Yang1, Lin Huang1, Tianxin Cong1, Qingfang Li1 and Meng Qiu1,2

1 West China School of Medicine/West China Hospital, Sichuan University, Chengdu, China

2 Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

* These authors have contributed equally to this work

Correspondence to:

Meng Qiu, email:

Keywords: colorectal cancer, platelet-lymphocyte ratio, prognosis, clinical features, meta-analysis

Received: November 14, 2016 Accepted: January 24, 2017 Published: March 08, 2017

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the prognostic and clinical value of platelet-lymphocyte ratio (PLR) in colorectal cancer was still unclear, which attracted more and more researchers’ considerable attention. We performed a systematic review and meta-analysis to investigate the relationship between PLR and survival as well as clinical features of CRC update to September 2016. The hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) were calculated to access the association. We included 24 eligible studies with a total of 13719 patients. Elevated PLR predicted shorter overall survival (OS) (HR=1.47; 95%CI, 1.28-1.68; p<0.001), poorer disease-free survival (DFS) (HR=1.51; 95% CI, 1.2-1.91; p=0.001), and worse recurrence-free survival (RFS) (HR=1.39; 95% CI, 1.03-1.86; p=0.03), but had nothing to do with Cancer-specific survival (CSS) (HR=1.14; 95% CI, 0.92-1.42; p=0.223). After trim and fill method, the connection between PLR and DFS disappeared (HR=1.143; 95%CI, 0.903-1.447; p=0.267). By subgroup analyze, we found that increased PLR predicated a worse OS and DFS in patients who underwent surgery, and this prognostic role also shown both in metastatic and nonmetastatic patients. In addition, elevated PLR was associated with poorly differentiated tumor (OR=1.51; 95% CI, 1.26-1.81; p<0.001), higher tumor stage (OR=1.25; 95% CI, 1.05-1.49; p=0.012), lymphovascular invasion (LVI) (OR=1.25; 95% CI, 1.09-1.43; p=0.001), and the recurrence of CRC (OR=2.78; 95% CI, 1.36-5.68; p=0.005). We indicated that pretreatment PLR was a good prognostic marker for CRC patients. High PLR was related to worse OS, RFS and poor clinical characteristics.


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Introduction

Colorectal cancer (CRC) caused almost 700,000 deaths worldwidely every year, making it the world’s fourth most deadly cancer [1]. It was the third most commonly diagnosed cancer in males and the second in females, with an estimated 1.4 million cases and 693,900 deaths occurring in 2012 [2]. The lifestyle changes in past low-CRC-risk countries resulted in rapid growth of colorectal cancer and the 5-year survival rate was still poor despite the progress of the treatment [3-6]. Pretreatment predicting indexes are in dire need to forecast potential of the tumor recurrence and prognosis for that the majority of the available prognostic markers are assessed postoperatively. The clinical and pathological TNM stages, the number of resected lymph nodes (nLNs), carcino-embryonic antigen (CEA), the lymphovascular invasion (LVI), the perineural invasion, in addition to some molecular markers (eg. PinX1, RAS, BRAF, MMR and so on) have all been identified as prognostic factors [7-11], however several weaknesses limited their application in routine clinical practice, such as high costs, lack of standardization, low consistency, and poor reproducibility [7, 12, 13, 14]. Therefore, finding a proper prognostic factors to assist coloractal cancer patients in guiding appropriate treatment to improve the therapeutic effectiveness is extremely urgent.

Prior studies showed that systemic inflammatory response (SIR) status played a vital role in tumor progression and therapeutic response [15-19]. The levels of platelets and lymphocytes represents the systemic inflammatory response (SIR), and they are easily obtained by widely used peripheral blood test. Platelet-lymphocyte ratio (PLR) as a combination of these two factors has been reported to be associated with poor prognosis in different tumor types, including CRC [20-32], but some other studies drew a different conclusion [33-43]. In brief, independent research results of the relationship between PLR and its impact on survival and clinical features were still inconsistent, partly due to limited published studies previously, various confounding factors and less detailed analysis. Recently, a lot of new studies on this issue were published continuously. Thus the aim of our study was to perform a systemic review and meta-analysis with all eligible current evidence to clarify this relationship and to evaluate whether PLR was an independent risk factors for the prognosis of patients with colorectal cancer.

Results

Literature search and study selection

A total of 194 relevant publications were initially retrieved. Of these, 29 duplicates were removed, 134 publications were excluded because the studies were animal experiment, literature reviews, comments, letters, or unrelated studies based on the titles and abstracts screening. After reading the full text, 7 publications were excluded due to irrelevant publications, studies with overlapping case series or lack of sufficient data for analysis, Therefore, a total of 24 publications with 13719 patients were included [20-43]. All of these studies contained the required information and evaluated the correlation between PLR and the prognosis of CRC. Figure 1 presents a summary of the study selection process.

Study characteristics

The main features of the 24 selected studies are shown in Table 1. From the 24 studies, fourteen publications were originated from the Asian (eight from China, three from Korea, three from Japan), nine were performed in Caucasian population (four from the UK, one from Hungary, one from Canada, one from Australia, one from Austria, one from Italy), and one from USA with mixed races. The OS was investigated in 22 studies, the DFS rate was analyzed in 12 studies, the CSS rate was evaluated in 4 studies, and the RFS rate was reported in 2 studies. These eligible studies were published from 2012 to 2016. Thirteen of these directly provided HR in multivariate analysis, and survival data of nine studies were extracted from univariate analysis while survival data of two studies were extracted from survival curves. The extracted data in detail were presented in Supplementary Table S1 and S2, while detailed NOS scores of each included study were presented in Supplementary Table S4.

Table 1: Study characteristics

Author

Year

Country

Ethnicity

Location

Na

Sex(male/female)

Stage

Metastasis

Treatmentb

Survival analysis

Analysis

NOS score

Azab

2014

USA

Mixed

Colorectal cancer

580

273/307

I/II/III/IV

Y

Surgery

OS/DFS

M/M

8

Baranyai

2014

Hungary

Caucasian

Colorectal cancer

336

180/156

I/II/III/IV

N

Surgery

OS/DFS

U/U

5

Baranyai

2014

Hungary

Caucasian

Colorectal cancer

118

80/38

IV

Y

Surgery

OS

U

5

Carruthers

2012

UK

Caucasian

Rectal cancer

115

75/40

I/II/III

Y

Surgery

OS/DFS

U/U

6

Chan

2016

Australia

Caucasian

Colorectal cancer

1623

801/882

I/II/III

N

Surgery

OS

U

8

Choi

2015

Canada

Caucasian

Colorectal cancer

549

296/253

I/II/III

N

Surgery

OS/RFS

U/U

8

He

2013

China

Asian

Colorectal cancer

243

155/88

IV

Y

Non surgery

OS

M

8

Kwon

2012

Korea

Asian

Colorectal cancer

200

123/77

I/II/III/IV

Y

Surgery

OS

M

8

Li

2016

China

Asian

Rectal cancer

140

81/59

I/II/III

N

Surgery

OS/DFS

U/U

7

Li

2016

China

Asian

Colorectal cancer

5336

3167/2169

I/II/III

Y

Surgery

OS/DFS

M/M

6

Li

2015

China

Asian

Colon cancer

110

58/52

IV

Y

Surgery

OS

M

7

Mori

2015

Japan

Asian

Colorectal cancer

157

87/65

I/II/III

N

Surgery

DFS

U

6

Neal

2015

UK

Caucasian

Colorectal cancer

302

192/110

IV

Y

Surgery

OS/CSS

U/U

7

Neofytou

2014

UK

Caucasian

Colorectal cancer

140

88/52

IV

Y

Surgery

OS/DFS

M/M

9

Neofytou

2015

UK

Caucasian

Colorectal cancer

140

88/52

IV

Y

Surgery

CSS

U

9

Ozawa

2015

Japan

Asian

Colorectal cancer

234

142/92

II

N

Surgery

DFS/CSS

M/M

7

Passardi

2016

Italy

Caucasian

Colorectal cancer

289

174/115

I/II/III/IV

Y

Non surgery

OS

M/

7

Son

2013

Korea

Asian

Colon cancer

624

368/256

I/II/III

N

Surgery

OS/DFS

M/M

7

Song

2015

Korea

Asian

Colorectal cancer

177

83/94

IV

N

Non surgery

OS

U

5

Sun

2014

China

Asian

Colon cancer

255

135/120

I/II/III

N

Surgery

OS/DFS

M/M

7

Szkandera

2014

Austria

Caucasian

Colon cancer

372

217/155

II/III

N

Surgery

OS

M

7

Toiyama

2013

Japan

Asian

Rectal cancer

84

62/22

I/II/III

N

Surgery

OS/DFS

U/U

6

Ying

2014

China

Asian

Colorectal cancer

205

144/61

I/II/III

N

Surgery

OS/CSS/RFS

M/M/M

7

You

2016

China

Asian

Colorectal cancer

1314

785/529

I/II/III/IV

Y

Surgery

OS

M

6

Zou

2016

China

Asian

Colorectal cancer

216

137/79

I/II/III/IV

Y

Surgery

OS/DFS

M/M

7

a Number of included patients.

bUnsurgery includes patients undergoing chemotherapy, chemoradiotherapy, or other treatment, but not doing surgery. Surgery including patients getting surgery with or without other treatment.

Abbreviations: NA: not available; OS: overall survival; DFS: disease-free survival; CRM: cancer-ralated mortality; TLR: Time to local recurrence; RFS: recurrence-free survival; CSS: Cancer-specific survival; M: multivariate analysis; U: univariate analysis; NOS: Newcastle-Ottawa Quality Assessment Scale; PLR: platelet-lymphocyte ratio.

Flow chat of literature search and study selection.

Figure 1: Flow chat of literature search and study selection.

Prognostic value of PLR for CRC patients

Twenty-two studies containing 13328 CRC patients reported the impact of PLR on OS, which showed the existence of heterogeneity across the studies (I2 = 58.6%, Ph < 0.001). We detected that higher PLR predicate shorter OS for CRC patients (HR = 1.47; 95%CI, 1.28-1.68; p < 0.001)(Table 2, Figure 2a). Furthermore, twelve studies containing 8217 CRC patients suggested that elevated PLR was significantly associated with a poor DFS (HR = 1.51; 95% CI, 1.20-1.91; p = 0.001) (Figure 2b). Increased PLR predicated a worse RFS (HR = 1.39; 95% CI, 1.03-1.86; p = 0.001) in the combination of 2 studies containing 754 CRC patients, however it was not related to CSS (HR = 1.14; 95% CI, 0.92-1.42; p = 0.223) (Table 2) in the combination of four studies containing 881 CRC patients.

Table 2: The pooled data on survival of meta-analysis

Variables

Na

Caseb

Pooled data

Heterogeneity

Na

Caseb

Pooled data

Heterogeneity

HR(95%CI)

P

I2

Ph

HR(95%CI)

P

I2

Ph

Overall survival

Disease-free survival

Overall

22

13328

1.47(1.28,1.68)

<0.001

58.60%

<0.001

12

8217

1.51(1.2,1.91)

0.001

68.10%

<0.001

By ethnicity

Caucasian

9

3844

1.6(1.3,1.96)

<0.001

60.00%

0.01

3

591

1.9(1.06,3.4)

0.031

73.40%

0.023

Asian

12

8904

1.41(1.17,1.7)

0.001

57.00%

0.008

8

7046

1.37(1.06,1.78)

0.017

60.80%

0.013

Mixed

1

580

1.12(0.71,1.77)

0.629

/

/

1

580

1.35(0.9,2.03)

0.148

/

/

By analysis method

Univariate

10

3687

1.57(1.26,1.96)

<0.001

70.70%

<0.001

5

832

1.96(1.31,2.94)

0.011

50.90%

0.087

Multivariate

12

9641

1.32(1.17,1.48)

<0.001

41.00%

0.068

7

7385

1.27(1.02,1.6)

0.036

57.50%

0.028

By treatment

Surgery

19

12619

1.51(1.3,1.74)

<0.001

55.1%

0.002

12

8217

1.51(1.2,1.91)

0.001

68.10%

<0.001

Non surgery

3

709

1.31(0.9,1.89)

0.157

71.2%

0.031

By cut-off

Single cut-off

15

10257

1.61(1.36,1.89)

<0.001

47.90%

0.02

10

7382

1.69(1.28,2.22)

0.001

67.70%

0.001

Multiple cut-offs

7

3071

1.27(1.03,1.56)

0.026

62.50%

0.014

2

835

1.04(0.65,1.67)

0.856

69.50%

0.07

<200

7

1043

1.50(1.24,1.81)

<0.001

3.40%

0.4

6

870

1.72(1.34,2.2)

<0.001

<0.01%

0.553

≥200

15

12245

1.44(1.22,1.71)

<0.001

68.10%

<0.001

6

7347

1.36(0.99,1.87)

0.059

77.90%

<0.001

By sample size

<200

7

884

1.8(1.44,2.26)

<0.001

<0.01%

0.698

5

636

1.62(1.2516,2.11)

<0.001

<0.01%

0.653

≥200

15

12444

1.39(1.19,1.63)

<0.001

66.00%

<0.001

7

7581

1.46(1.06,2.01)

0.019

78.10%

<0.001

By study result

Positive

11

5007

1.57(1.41,1.74)

<0.001

12.80%

0.325

5

887

1.65(1.32,2.05)

<0.001

2.50%

0.392

Negative

11

8221

1.29(1.05,1.59)

0.016

62.50%

0.002

7

7330

1.36(0.99,1.87)

0.058

73.20%

0.001

By metastatic

Yes

12

8963

1.34(1.16,1.54)

<0.001

38.70%

0.083

5

6387

1.17(1.04,1.33)

0.012

13.80%

0.327

No

10

4365

1.62(1.27,2.06)

0.001

65.30%

0.002

7

1830

1.89(1.15,3.08)

0.011

77.00%

<0.001

By location

Colorectal cancer

15

11628

1.47(1.26,1.71)

<0.001

64.40%

<0.001

7

6999

1.71(1.23,2.37)

0.001

76.80%

<0.001

Rectal cancer

3

339

1.65(1.17,2.34)

0.005

<0.01%

0.914

3

339

1.5(1.07,2.08)

0.017

<0.01%

0.615

Colon cancer

4

1361

1.49(0.92,2.4)

0.183

69.40%

0.02

2

879

0.89(0.65,1.21)

0.45

42.70%

0.186

By NOS

<6

3

631

2.02(1.06,3.87)

0.034

74.00%

0.021

1

336

3.4(2.0,5.79)

<0.001

/

/

≥6

19

12597

1.34(1.24,1.45)

<0.001

43.50%

0.023

11

7881

1.35(1.11,1.65)

0.002

50.90%

0.026

Cancer-specific survival

Recurrence-free survival

Overall

4

881

1.14(0.92,1.42)

0.223

63.70%

0.041

2

754

1.39(1.03,1.86)

0.03

13.50%

0.282

a Numbers of studies included in the meta-analysis.

b Number of patients of included studies.

Abbreviations: NA: not available; HR: hazard ratio; 95%CI: confidence interval; P: p value of pooled HR; I2: value of Higgins I-squared statistics; Ph: p value of Heterogeneity test.

To explain the source of heterogeneity, we further performed a subgroup analysis by ethnicity, analysis method, major treatment therapy, respective cut-off value, sample size, metastasis status, tumor location and NOS score. The higher PLR was, the shorter OS and DFS were showed both in Caucasian ( [OS: HR = 1.6; 95% CI, 1.3-1.96; p < 0.001]; [DFS: HR = 1.9; 95% CI, 1.06-3.4; p = 0.031]) and Asian groups ( [OS: HR = 1.41; 95% CI, 1.17-1.7; p = 0.001]; [DFS: HR = 1.37; 95% CI, 1.06-1.78; p = 0.017]). Significant association were detected whether univariate analysis ( [OS: HR = 1.57; 95% CI, 1.26-1.96; p < 0.001]; [DFS: HR = 1.96; 95% CI, 1.31-2.94; p = 0.011]) or multivariate ( [OS: HR = 1.32; 95% CI, 1.17-1.48; p < 0.001]; [DFS: HR = 1.27; 95% CI, 1.02-1.6; p = 0.036]) analysis were used in original studies. Elevated PLR was strongly associated with poor OS in patients who underwent surgical resection ( [OS: HR = 1.51; 95% CI, 1.3-1.74; p < 0.001]), but not in nonsurgery subgroup which involved limited studies ( [OS: HR = 1.31; 95% CI, 0.9-1.89; p = 0.157]) (Figure 3a). After enlarging the sample size by meta-analysis, we overthrow the old conclusion in the negative study result subgroup that PLR had nothing to do with OS. For metastatic colorectal cancer patients, increased PLR predicated a worse OS and DFS ( [OS: HR = 1.34; 95% CI, 1.16-1.54; p < 0.001]; [DFS: HR = 1.17; 95% CI, 1.04-1.33; p = 0.012]), and this prognostic implication also existed in nonmetastatic CRC ( [OS: HR = 1.62; 95% CI, 1.27-2.06; p = 0.001]; [DFS: HR = 1.89; 95% CI, 1.15-3.08; p = 0.011]) (Figure 3b). Significant association were almost detected in all stratified analysis which further proved our results. More details about the subgroup analysis of OS and DFS were presented in Table 2.

Figure 2:

Figure 2: Results of prognostic analysis for PLR in CRC for OS a. and DFS b.

Figure 3:

Figure 3: Association between PLR and OS stratified by treatment a., metastatic b.

PLR and clinical characteristics of CRC patients

In addition, we examined the association between PLR and the clinical parameters of colorectal cancer (Table 3). Peripheral higher PLR was detected to be associated with gender(OR = 0.8; 95% CI, 0.72-0.90; p < 0.001), cancer location(OR = 1.54; 95% CI, 1.19-1.99; p = 0.001), poorer differentiation status (OR = 1.51; 95% CI, 1.26-1.81; p < 0.001), higher tumor stage(OR = 1.25; 95% CI, 1.05-1.49; p = 0.012), higher T (OR = 2.13; 95% CI, 1.36-3.34; p = 0.001) stage and N stage(OR = 1.35; 95% CI, 1.17-1.54; p < 0.001), more lymphovascular invasion (OR = 1.25; 95% CI, 1.09-1.43; p = 0.001), and recurrence(OR = 2.78; 95% CI, 1.36-5.68; p = 0.005) in colorectal cancer patients (Figure 4).

Table 3: The pooled data on clinical characteristics of included studies

Variables

Na

Caseb

Pooled data

Heterogeneity

OR(95%CI)

P

I2

Ph

Gender

13

9483

Female

3908

Reference

Male

5575

0.8(0.72,0.90)

<0.001

<0.01%

0.512

Location

9

8262

Rectaum

4261

Reference

Colon

4001

1.54(1.19,1.99)

0.001

51.80%

0.034

Differentiation

8

7388

Well and moderately

6526

Reference

Poorly

862

1.51(1.26,1.81)

<0.001

28.30%

0.202

Stage

7

3156

I/II

1770

Reference

III/IV

1386

1.25(1.05,1.49)

0.012

46.00%

0.085

T

7

6419

1,2

1516

Reference

3,4

4903

2.13(1.36,3.34)

0.001

51.10%

0.056

N

6

6583

Negative(N0)

3504

Reference

Positive(N1,2)

3079

1.35(1.17,1.54)

<0.001

22.80%

0.262

LVI(lymphovascular invasion)

6

7951

No

5733

Reference

Yes

2218

1.25(1.09,1.43)

0.001

<0.01%

0.933

Recurrence

2

236

Absent

192

Reference

Present

44

2.78(1.36,5.68)

0.005

<0.01%

0.352

Chemotherapy

4

6670

No

2214

Reference

Yes

4456

1.09(0.74,1.61)

0.674

72.00%

0.013

a Numbers of studies included in the meta-analysis.

b Number of patients of included studies.

Abbreviations: LVI: lymphovascular invasion; OR: odds ratio; 95%CI: confidence interval; P: p value of pooled HR; I2: value of X2 based I-squared statistics; Ph: p value of Heterogeneity test.

Figure 4:

Figure 4: Association between PLR and tumor location a., differentiation b., stage c. and lymphovascular invasion d.

Sensitivity analysis and publication bias

To identify the source of heterogeneity across selected studies, sensitivity analysis was conducted by removing each study in turn from the analysis. The pooled ORs and HRs were not significantly changed, indicating the stability of our analyses. The funnel plots were largely symmetrical for OS in patients with CRC, and the results of the Begg’s and Egger’s tests showed no evidence of significant publication bias among the included studies (OS: Begg’s test Pr > |z| = 0.159, Egger’s test P > |t| = 0.130) (Figure 5a). But slight publication bias was seen in DFS (DFS: Begg’s test Pr > |z| = 0.064, Egger’s test P > |t| = 0.013). So a trim and fill method was used to estimate the asymmetry in the funnel plot (HR = 1.143; 95%CI, 0.903-1.447, p = 0.267)(Figure 5b).

Figure 5:

Figure 5: Egger’s test for accessing publication biases for role of PLR on OS a. and DFS (b., after trim and fill method).

Discussion

This systematic review and meta-analysis, including 24 individual studies of 13719 patients, found that increased PLR was strongly associated with poor overall survival and recurrence-free survival in patient with colorectal cancer. However, PLR was unrelated to cancer-specific survival and disease-free survival after trim and fill method. The stratified analyses showed that elevated PLR was associated with poor outcome in both Caucasian and Asian population, univariate and multivariate analysis, metastatic and nonmetastatic CRC, and resected patients. However, we did not observe the significant association in nonsurgery subgroup for that the number of the included original studies in this subgroup is limited. For the negative study result subgroup, the HR of OS was 1.29 (95% CI, 1.05-1.59; p = 0.016), which meaned that after enlarging the sample size by meta-analysis, we overthrow the old conclusion that PLR had nothing to do with OS. Our finding confirmed the hypothesis that PLR was an appropriate prognostic factor for CRC patient survival.

Cancer progression and prognosis was determined not only by tumor characteristics but also by the host inflammatory response [44, 45]. Using clinical, inflammatory, and molecular biomarkers as CRC prognostic factors are increasingly interesting, but there remained a lack of reliable, reproducible, and low-cost markers that can be readily incorporated into routine practice to optimally predict prognosis and guide treatment [31]. Some combinations of the inflammatory response parameters (eg. lymphocytes, neutrophils, platelets and acute-phase proteins, which are simple and easy to measure using standardized and widely used assays) including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and albumin/globulin ratio (AGR), have been performed to evaluate the prognosis in various cancers, including CRC, and so on [27, 33, 46-48]. There were many reasons for PLR’s ideal prognostic role in CRC patient. Firstly, platelets secrete several tumor growth and angiogenic factors, which might influence tumor progression [49]. Secondly, while in antitumor reaction of the immune system, the CD8+ and CD4+ T-lymphocyte interaction among each other can induce tumor cell apoptosis, which can improve the survival of CRC patients for the chemotherapy efficacy [50]. These supported our finding that the PLR was a promising prognostic factors for the survival of CRC patients, which was consistent with previous meta-analysis [51-54], however, our study was to some extent superior to the previous studies because of much more included studied and patients, more detailed analyses and less limitation. We included all current eligible relative studies by systemic review and meta-analysis. We did subgroup analyses to explore the heterogeneity sources, besides we explored the relationship between PLR and the inferior clinical features.

By analyzing clinical factors, we found the relationship between the increased PLR and the clinical characteristics of CRC patients. PLR tended to be higher in colon cancer than rectum which need further explanation. Poorly differentiated cancer always accompanied with elevated PLR, for that poorly differentiated tumour cells growing faster with angiogenic and tumour growth factors secreted by platelet cell, such as platelet factor 4 (PF4), thrombospondin, vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF) [36]. Moreover, platelets reflected the invasive potential of CRC and was closely associated with lymphovascular invasion (LVI) [55]. PLR was a good prognostic marker in mCRC patients, because several studies have shown that platelets induce circulating tumor cell epithelial-mesenchymal transition and promote extravasation to metastatic sites [43, 56, 57]. Lymphocytes were involved in cancer immune surveillance which influenced the tumor recurrence to some extent [58]. Our study results indicated that the relationship between PLR and some clinical factors presented a new researching direction for future research. Moreover, the easily got PLR can be used to reflect some clinical characteristics which were difficult to obtain like tumour differentiation, lymphovascular invasion (LVI), recurrence and so on. Pretreatment blood test for PLR played a vital role in assessment of cancer characteristics and patients prognosis.

There were limitations in our systematic review. First, the included studies were almost retrospective studies and more studies with prospective design were warranted in future. Second, eleven enrolled studies applied univariate analysis only (without providing multivariate analysis data), while subgroup analysis showed the prognostic values of PLR existed in these studies. Moreover, there are significant heterogeneity existing in OS and DFS analysis. Therefore additional large cohorts of prospective studies are needed to correct for heterogeneity.

In conclusion, peripheral blood PLR was an effective prognostic marker for CRC patients. Elevated PLR was related to worse overall survival and recurrence-free survival, but not for disease-free survival and cancer-specific survival. The prognostic utility of PLR might help to guide use of individual therapies and patient counselling in future.

materials and Methods

Search strategy

PubMed, Web of Science and Embase were searched from inception to September 2016. The search strategy used the keywords as follows: “PLR” or “platelet lymphocyte ratio” or “platelet to lymphocyte ratio” or “platelet-lymphocyte ratio” or “platelet lymphocyte” and “CRC” or “colon neoplasm” or “rectal neoplasm” or “colorectal neoplasm” or “colorectal tumor” or “colorectal cancer” or “colorectal carcinoma”. There was no language restriction in our study. References of relevant studies and review articles were searched for potential eligible studies.

Inclusion and exclusion criteria

The inclusion criteria in this meta-analysis study were as follows: (1) studies investigated the relationship between PLR and colorectal cancer prognosis or clinical characteristics; (2) the PLR was obtained from a preoperative peripheral blood test; (3) adequate data were provided to measure odds ratio (OR) and hazard ratios (HRs) with 95% confidence intervals (CIs). The exclusion criteria were as follows: (1) unrelated studies, animal experiment, cell experiment, literature reviews, comments, letters, meta analysis, or case reports; (2) studies without sufficient data for analysis; and (3) duplicated publications. When studies with overlapping cases were met, the study with the larger number of patients was included.

Data collection and quality assessment

Relevant datas were professionally extracted by two authors independently, and disagreements were resolved through discussion with a third author. Data collected from each study included first author, publication year, country and ethnicity of the study participants, number of patients, tumor characteristics (stage, location, size, differentiation, lymphovascular invasion, treatment, recurrence), cut off value for high or low PLR, and survival data (OS/DFS/CSS/RFS). If some publications provided survival data by Kaplan-Meier curves indirectly, Engauge Digitizer version 4.1 was applied to extract the data. The quality of included articles were assessed using the Newcastle-Ottawa Scale (NOS) by two authors independently (Supplementary Table S2 showed the Newcastle-Ottawa quality assessment scale). The total scores of NOS ranged from 0 to 9, with higher scores indicating better quality. A high-quality study was defined as the study with ≥6 points on NOS.

Statistical analysis

According to the cut-off values, PLR was devided into high or low level groups in each study, and the hazard ratio with the 95% confidence interval (high vs low level of PLR) were used to evaluate the relationship between PLR and long-term prognosis (OS/DFS/CSS/RFS). Odds ratio and 95%CI were pooled to access the role of PLR on clinical features of colorectal cancer. Statistical heterogeneity was evaluated by Q and I2 tests, and if the p-value < 0.1 or I2 > 50%, which suggested the existence of substantial heterogeneity, thus we used a random-effect model to calculate the pooled estimate. Otherwise, the fixed-effect model would be applied instead. The subgroup analyses were applied to explore the heterogeneity sources. Publication bias was evaluated using the Egger’s weighted linear regression and Begg’s regression method. A trim and fill method was used when significant publication bias existed. All statistical tests were two-sided, and a p value < 0.05 was considered to be statistically significant. All analyses were conducted by Stata 14.0 (STATA Corporation, College Station, TX, USA).

Abbreviations

CRC, colorectal cancer; PLR, platelet-lymphocyte ratio; HR, hazard ratio; OR, odds ratio; 95% CI, 95% confidence interval; OS, overall survival; DFS, disease-free survival; RFS, recurrence-free survival; CSS, Cancer-specific survival; NOS, the Newcastle-Ottawa Scale; Ph, P-value of heterogeneity.

Authors’ contributions

N. C., WL. L. and M. Q. conceived the study idea and designed the study. KX. H. and WH. Y. reviewed the literature and Collected the data. L.H. performed statistical analyses. N. C., and WL. L. drafted the manuscript. TX. C. and QF. L. reviewed and edited the manuscript. All authors read and approved the final manuscript.

Conflicts of interests

The authors have declared no conflict of financial interest.

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