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Prognostic significance of pretreatment elevated platelet count in patients with colorectal cancer: a meta-analysis

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Oncotarget. 2016; 7:81849-81861. https://doi.org/10.18632/oncotarget.13248

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Yu Long _, Ting Wang, Qian Gao and Chengya Zhou

Abstract

Yu Long1, Ting Wang1,2, Qian Gao3, Chengya Zhou1

1Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

2Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China

3Oncology Department, Du Jiang Yan Medical Center, Chengdu, Sichuan, China

Correspondence to:

Ting Wang, email: [email protected]

Keywords: colorectal cancer, platelet, thrombocytosis, prognosis, meta-analysis

Received: October 05, 2016     Accepted: October 24, 2016     Published: November 09, 2016

ABSTRACT

Background: The prognostic effect of pretreatment elevated platelet count remains controversial in colorectal cancer patients. We conducted this meta-analysis to evaluate the prognostic impact of it in these patients.

Methods: PubMed, EMBASE and Cochrane Library were searched and studies on the prognostic significance of pretreatment elevated platelet count in colorectal patients were identified. We performed the meta-analysis, using overall survival and disease-free survival as outcomes and presenting data with hazard ratio and its 95% confidence interval. Heterogeneity among studies and publication bias were also evaluated.

Results: Thirty studies were included in the meta-analysis. Compared with normal platelet count, pretreatment elevated platelet count was associated with poorer overall survival (Hazard ratio = 1.837, 95% confidence interval, 1.497 to 2.255, p = 0.000) and poorer disease-free survival (Hazard ratio = 1.635, 95% confidence interval, 1.237 to 2.160, p = 0.001) in patients with colorectal cancer. In subgroup analyses, pretreatment elevated platelet count was also associated with poorer overall survival and disease-free survival in most subgroups.

Conclusion: Pretreatment elevated platelet count was an independent prognostic factor of overall survival and disease-free survival in colorectal cancer patients. Large-scale prospective studies and a validation study are warranted.


INTRODUCTION

Colorectal cancer is 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 [1]. Several markers like carcinoembryonic antigen, C-reactive protein, albumin and tumor necrosis factors have been reported as prognostic indicators of outcomes in patients with colorectal cancer. However, it is still difficult to predict the outcome of patients before treatment.

There is a growing body of evidence showing that elevated platelet count or thrombocytosis is associated with outcomes of colorectal cancer [210]. Early in 1998, Monreal M et al. reported a significant association between pre-operative platelet count and survival in patients with colorectal cancer. The following studies confirmed this association [2, 3, 5, 6]. However, some other studies failed to demonstrate the association between pretreatment elevated platelet count and outcomes of colorectal cancer [1116]. Considering the controversial evidence, we conduct a meta-analysis to evaluate whether pretreatment elevated platelet count is a prognostic marker of colorectal cancer.

RESULTS

Study selection

Electronic search identified 2604 potentially relevant references. Additional 5 references were further identified by checking the reference list. 2469 duplicates or clearly irrelevant references were excluded through reading the abstracts. 140 references were read in full and 106 references were excluded for irrelevance or lack of data on comparisons or outcomes. Four references were excluded for repeated data. Finally, 30 references fulfilled the inclusion criteria and provided data for the meta-analysis [231] (Figure 1).

Flowchart of the process for the identification of relevant studies.

Figure 1: Flowchart of the process for the identification of relevant studies.

Characteristics of included studies

All thirty included articles were cohort studies published from 1998 to 2016. This meta-analysis included 9123 patients. The quality score of included studies ranged from 6 to 8 stars. Hazard ratios of overall survival were available in 28 included studies and hazard ratios of disease-free survival were available in 15 included studies. Characteristics of the included studies are listed in Table 1.

Table 1: Characteristics of included studies

Study

Number of patients

Tumor type

Disease stage

Cut-off value

Area

Study time

Age (year)

Follow-up (year)

Treatment

Outcome

Quality score

Azab B 2014 [11]

580

colorectal cancer

I-IV

tertile

USA

2005-2011

68.6

40.5

surgery or chemotherapy

overall survival, disease-free survival

6

Baranyai Z 2014 [2]

336

colorectal cancer

I-IV

400

Hungary

2001-2011

67

36.1

surgery

overall survival, disease-free survival

8

Carruthers R 2012 [17]

115

rectal cancer

I-III

NA

UK

2000-2005

63.8

37.1

chemoradiation and surgery

overall survival, disease-free survival

6

Chen LL 2016 [3]

503

colorectal cancer

I-IV

300

China

2010-2013

58

33.8

surgery

overall survival

7

Choi KW 2014 [12]

105

colorectal cancer

I-IV

400

Korea

2005-2008

63

44

surgery

overall survival

7

Cravioto-Villanueva A 2012 [4]

163

rectal cancer

I-III

350

Mexico

2000-2007

57.6

35.4

chemoradiation and surgery

overall survival

6

Del Prete M 2015 [18]

208

colorectal cancer

IV

0.54 ULN

Italy

NA

61

NA

chemotherapy

overall survival

6

Guo T 2014 [5]

310

colorectal cancer

I-III

400

USA

2004-2013

69.9

NA

NA

overall survival

6

Jósa V 2015 [19]

336

colorectal cancer

I-IV

400

Hungary

2001-2011

66.9

NA

surgery and chemotherapy

overall survival

6

Jósa V 2015 [19]

166

colorectal cancer

IV

380

Hungary

2001-2011

62

28

surgery and chemotherapy

overall survival, disease-free survival

6

Kandemir EG 2005 [7]

198

colon cancer

I-II

400

Turkey

NA

57

47

NA

overall survival, disease-free survival

7

Kaneko M 2012 [20]

50

colorectal cancer

IV

400

Japan

2005-2010

61

17

chemotherapy

overall survival,

7

Kawai K 2013 [8]

108

rectal cancer

I-IV

365

Japan

2003-2012

63.3

22.5

chemoradiation and surgery

disease-free survival

7

Kim HJ 2015 [9]

314

rectal cancer

I-III

370

Japan

2003-2011

NA

36

chemoradiation and surgery

overall survival, disease-free survival

7

Kozak MM 2015 [21]

129

colorectal cancer

I-III

400

USA

2005-2009

67

24.7

chemotherapy

overall survival, disease-free survival

7

Kronborg CS 2015 [13]

314

colorectal cancer

IV

400

Denmark

2007-2011

64.5

21.3

chemotherapy

overall survival

7

Lee YS 2016 [22]

284

colorectal cancer

II

450

Korea

2003-2009

65

7.67

Adjuvant therapy

overall survival, disease-free survival

8

Lin MS 2012 [23]

150

colorectal cancer

I-IV

300

China

2006-2011

60.9

NA

surgery or NA

overall survival

6

Monreal M 1998 [24]

180

colorectal cancer

I-III

quertile

Spain

1994-1996

67

13

surgery and chemotherapy

overall survival

7

Neal CP 2015 [25]

302

colorectal cancer

IV

400

UK

2006-2010

64.8

29.7

surgery

overall survival

7

Paik KY 2014 [26]

600

colorectal cancer

I-IV

400

Korea

2006-2009

62.3

27.4

surgery

overall survival, disease-free survival

8

Qiu MZ 2010 [27]

363

colorectal cancer

I-IV

400

China

2005-2009

56

26

NA

overall survival

7

Roxburgh CS 2010 [28]

287

colon cancer

I-III

400

UK

1997-2005

NA

65

surgery and chemotherapy

overall survival

7

Sasaki K 2012 [29]

636

colorectal cancer

I-IV

370

Japan

2002-2008

65.9

49.1

surgery and chemotherapy

overall survival, disease-free survival

8

Shen L 2014 [14]

199

rectal cancer

II-III

300

China

2006-2011

55

31

chemoradiation and surgery

overall survival, disease-free survival

8

Song A 2015 [15]

177

colorectal cancer

IV

400

South Korea

2006-2013

52

3.1

chemotherapy

overall survival

7

Toiyama Y 2015 [30]

89

rectal cancer

I-III

300

Japan

2001-2012

65

56

chemoradiation and surgery

overall survival, disease-free survival

8

Wan S 2013 [31]

1513

colorectal cancer

I-IV

400

USA

1990-2010

64.9

54

surgery and chemotherapy

overall survival, disease-free survival

8

Wei Y 2015 [10]

286

colorectal cancer

II-III

276

China

2003-2011

62

34

surgery and chemotherapy

disease-free survival

7

Zhao H 2016 [16]

122

colorectal cancer

IV

300

China

2006-2009

NA

NA

chemotherapy

overall survival

7

NA, not available; ULN, upper limits of normal.

Prognostic impact of pretreatment elevated platelet count on overall survival

Twenty-eight studies contributed data to the analyses of overall survival [2-7, 9, 11-31]. Significant heterogeneity was found among studies (I2 = 81%, p = 0.000, Figure 2). Random-effect model was used. The pooled hazard ratio estimate showed that patients with pretreatment elevated platelet count had poorer overall survival compared with normal platelet count (HR = 1.837, 95% confidence interval, 1.497 to 2.255, p = 0.000, Figure 2).

Forest plot showing the prognostic effect of pretreatment elevated platelet count on overall survival of colorectal cancer patients.

Figure 2: Forest plot showing the prognostic effect of pretreatment elevated platelet count on overall survival of colorectal cancer patients. *CI: Confidence interval.

We performed subgroup analyses on confounding factors such as disease stage, cancer type, cut-off values, etc. The results consistently showed that patients with pretreatment elevated platelet count had poorer overall survival compared with normal platelet count in most subgroups: multivariate analysis subgroup (p = 0.000), univariate analysis subgroup (p = 0.000), preoperative subgroup (p = 0.000), metastatic disease subgroup (p = 0.027), stage I-III disease subgroup (p = 0.000), rectal cancer subgroup (p = 0.009), cut-off value ≥ 400 subgroup (p = 0.000), 300 ≤ cut-off value < 400 subgroup (p = 0.000), cut-off value < 300 subgroup (p = 0.043). In colon cancer subgroup, overall survival of patients with pretreatment elevated platelet count had no difference with patients with normal platelet count (p = 0.099). The detailed results of subgroup analyses were summarized in Table 2.

Table 2: Summarized results of meta-analysis

Outcomes

Subgroups

Analysis Model

Studies

Heterogeneity

Hazard Ratio

95% Confidence Interval

P-value

P-value

I-square %

Overall survival

total

random

28

0.000

81.006

1.837

1.497

2.255

0.000

multivariable

random

11

0.000

68.792

2.122

1.508

2.985

0.000

univariable

fixed

8

0.162

33.341

1.675

1.331

2.108

0.000

preoperative

random

20

0.000

83.380

2.015

1.547

2.625

0.000

metastatic disease

random

6

0.021

62.204

1.503

1.047

2.157

0.027

stage I-III disease

random

11

0.000

82.555

2.330

1.461

3.715

0.000

rectal cancer

random

5

0.008

70.832

2.796

1.286

6.078

0.009

colon cancer

random

2

0.088

65.731

2.594

0.837

8.035

0.099

cut-off value ≥ 400 × 109 / L

random

15

0.000

77.687

1.633

1.284

2.077

0.000

300 ≤ cut-off value < 400 × 109 / L

random

9

0.038

51.062

2.467

1.685

3.612

0.000

cut-off value < 300 × 109 / L

-

1

-

-

1.496

1.013

2.210

0.043

Disease-free survival

total

random

15

0.000

82.195

1.635

1.237

2.160

0.001

multivariable

random

6

0.000

90.188

2.166

1.234

3.802

0.007

univariable

random

9

0.008

61.329

1.377

0.992

1.909

0.056

preoperative

random

14

0.000

83.175

1.751

1.287

2.384

0.000

metastatic disease

-

1

-

-

0.850

0.540

1.320

0.459

stage I-III disease

random

8

0.000

78.468

1.697

1.154

2.495

0.007

rectal cancer

Fixed

5

0.194

34.037

1.588

1.175

2.147

0.003

colon cancer

-

1

-

-

4.102

1.822

9.235

0.001

cut-off value ≥ 400 × 109 / L

random

6

0.000

81.695

1.589

0.989

2.555

0.056

300 ≤ cut-off value < 400 × 109 / L

Fixed

6

0.076

49.840

2.030

1.599

2.578

0.000

cut-off value < 300 × 109 / L

-

1

-

-

1.853

1.236

2.780

0.003

Prognostic impact of pretreatment elevated platelet count on disease-free survival

Fifteen studies contributed data to the analyses of disease-free survival. Significant heterogeneity was found among studies (I2 = 82%, p = 0.000, Figure 3). Random-effect model was used. The pooled hazard ratio estimate showed that patients with pretreatment elevated platelet count had poorer disease-free survival compared with normal platelet count (HR = 1.635, 95% confidence interval, 1.237 to 2.160, p = 0.001, Figure 3).

Forest plot showing the prognostic effect of pretreatment elevated platelet count on disease-free survival of colorectal cancer patients.

Figure 3: Forest plot showing the prognostic effect of pretreatment elevated platelet count on disease-free survival of colorectal cancer patients. *CI: Confidence interval.

The results of subgroup analyses revealed that colorectal patients with pretreatment elevated platelet count had poorer disease-free survival compared with normal platelet count in the following subgroups: multivariate analysis subgroup (p = 0.007), preoperative subgroup (p = 0.000), stage I-III disease subgroup (p = 0.007), rectal cancer subgroup (p = 0.003), colon cancer subgroup (p = 0.001), 300 ≤ cut-off value < 400 subgroup (p = 0.000), cut-off value < 300 subgroup (p = 0.003). In three subgroups, patients with pretreatment elevated platelet count had similar disease-free survival compared with patients with normal platelet count: univariate analysis subgroup (p = 0.056), cut-off value ≥ 400 subgroup (p = 0.056) and metastatic disease subgroup (all patients received R0 resection of primary and metastasis tumors) (p = 1.320). The detailed results of subgroup analyses were summarized in Table 2.

Publication bias

Visual inspection of the funnel plot for overall survival and disease-free survival outcomes did not show the typically asymmetry associated with publication bias (Figure 4, Figure 5). Evidence of publication bias was also not seen with the Begg’s tests of overall survival (p = 0.441) and disease-free survival (p = 1.000).

Funnel plot showing the publication bias of overall survival.

Figure 4: Funnel plot showing the publication bias of overall survival.

Funnel plot showing the publication bias of disease-free survival.

Figure 5: Funnel plot showing the publication bias of disease-free survival.

Sensitivity analyses

The result of Sensitivity analyses demonstrated that no individual study had excessive influence on the stability of the pooled effect of comparisons for overall survival (Figure 6) and disease-free survival (Figure 7). The result of this meta-analysis is robust.

Forest plot showing the sensitivity analyses of overall survival.

Figure 6: Forest plot showing the sensitivity analyses of overall survival. *CI: Confidence interval.

Forest plot showing the sensitivity analyses of disease-free survival.

Figure 7: Forest plot showing the sensitivity analyses of disease-free survival. *CI: Confidence interval.

DISCUSSION

Elevated platelet count or thrombocytosis is observed in patients with various kinds of cancer and reported inversely correlated with survival [24, 3236]. It was reported that nearly 10% to 30% of patients with colorectal cancer had elevated platelet count before treatment and worse survival than those with normal platelet count [2-5, 7, 9, 21]. In our study, the results demonstrated that elevated platelet count was associated with shorter overall survival and disease-free survival in patients with colorectal cancer. Subgroup analyses demonstrated that the impact of elevated platelet count are consistent in different disease stages, tumor locations and analysis models. The result of our study is robust. This evidence indicated that platelet could be a simple and robust prognostic marker to identify high risk patients. Those patients should be taken into account to receive adjuvant therapy or maybe anti-platelet medications. There have been accumulating evidence that postdiagnosis aspirin therapy can improve overall survival of patients with colorectal cancer in recent years [37].

It is noteworthy that the cut-off values applied in included studies were not unified. Most studies used 400 × 109/L as cut-off value and some studies used 300 × 109/L. The optimal cut-off value, however, was not validated in previous studies. The subgroup analyses reached consistent results among different cut-off value subgroup. The cut-off value ≥ 400 × 109 / L and between 300 and 400 can both distinguished patients well by overall survival and disease-free survival. Only in cut-off value ≥ 400 × 109 / L subgroup, platelet count failed to predict the disease-free survival of patients (p = 0.056, Table 2). Regarding this, it may be reasonable to suggest that the cut-off value between 300 and 400 × 109 / L be applied in further investigation.

The mechanisms of tumor-related elevated platelet count or thrombocytosis remain undetermined. One of the potential hypotheses is that thrombocytosis is usually associated with inflammatory cytokines induced by interactions between tumor and host. Among these cytokines, IL-6, having multiple functions in many physiological conditions, plays a very important role in the formation of thrombocytosis [38]. By stimulating differentiation of megakaryocytes to platelets in the bone marrow, IL-6 induced thrombocytosis in various malignancies [39]. For another explanation of cancer-associated thrombocytosis, tumor can stimulate activation of platelet. As reported in several studies that cancer cells can secrete vascular endothelial growth factor to stimulates megakaryocyte differentiation [40]. For the prognostic association between elevated platelet count and patients’ outcomes, there is a most widely accepted hypothesis that activated platelets contribute to the tumor growth, angiogenesis and metastasis by releasing various cytokines with inflammatory, proliferative and angiogenic activity [4143]. With regard to tumor metastasis, platelets can cover and protect circulating tumor cells from the host’s immune system. With these underlying mechanisms, platelets may be a direct or indirect target for cancer therapy.

There are some limitations of this study. First, our analysis is based on low-level evidence retrospective studies, in most of which some important confounders were not well adjusted, such as tumor stage, therapeutic strategy or ratio of colon and rectal cancer. The result of subgroup analysis, however, demonstrated that the negative prognostic significance of thrombocytosis on overall survival and disease-free survival was consistent between groups. Subgroup analysis according to therapeutic strategies was not performed because of insufficient data. Second, the sample size of some included studies were very small. The results of subgroup analyses still confirm the prognostic significance of thrombocytosis. Third, although the platelet count is easy to measure, its utility as a clinical prognostic marker could be affected by some other conditions, such as thrombosis, coronary disease, splenic disease, myeloproliferative disease, blood coagulation disorders, iron deficiency anemia and drugs. Actually, some heterogeneity was unexplainable.

In conclusion, our study demonstrated that the pretreatment elevated platelet count was an independent prognostic factor of overall survival and disease-free survival in colorectal cancer patients. It may make sense that patients with elevated platelet count should receive intensive treatment or anti-platelet therapy. And large-scale prospective studies and a validation study are warranted to confirm its prognostic significance and determine the optimal platelet cut-off value.

MATERIALS AND METHODS

Eligibility criteria

This meta-analysis was performed according to the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [44]. Cohort studies, being published from inception to July 9, 2016, which reported comparisons of overall survival or disease-free survival between colorectal cancer patients with pretreatment elevated platelet count and those patients with pretreatment normal platelet count. The study participants had been pathologically diagnosed colorectal cancer patients.

Search strategy

An electronic search in PubMed, EMBASE and the Cochrane Library were conducted from inception to July 9, 2016. The following key words in combination as medical subject heading terms and text words were used: “colorectal cancer” and “platelet” or “thrombocytosis”. Potentially relevant articles were identified by reading titles and abstracts. The full texts of the relevant articles were read to determine whether they met the inclusion criteria. The references were also searched to identify relevant studies.

Quality assessment

For cohort studies, the 9-star Newcastle-Ottawa Scale was used to assess the risk of bias [45]. This scale is an 8-item instrument that allows for assessment of patient population and selection, study comparability, follow-up, and outcome. Interpretation of the scale is performed by awarding points for high-quality elements. Studies with 5 or more stars were defined as high-quality studies and were included.

Statistical analyses

Data was extracted using a unified form and study information including author name, study year, study area, sample size, hazard ratio of overall survival or disease-free survival were collected. If the hazard ratio was not reported in the original article, we would calculate hazard ratio from reported data according to the methods described by Tierney et al [46]. Statistical heterogeneity among studies was examined using the Cochrane Q test by calculating the I2 value [47]. The I2 value greater than 50% or p value less than 0.05 were considered to represent significant heterogeneity. The pooled hazard ratio and the 95% confidence interval were calculated using the Z test. The pooled hazard ratio and the 95% confidence interval were calculated using the Mantel-Haenszel formula (fixed-effect model) when heterogeneity was not detected (p > 0.05), or using the DerSimonian-Laird formula (random-effect model) when heterogeneity was significant (p < 0.05) [48]. Publication bias was evaluated using the funnel plot and the Begg’s test [49]. Influence analyses were conducted to access how robust the pooled estimators were by removing individual studies. An individual study was suspected of excessive influence if the point estimate of its omitted analysis was outside the 95% confidence interval of the combined analysis. Statistical analyses were performed with Comprehensive Meta Analysis professional version 2.2 (Biostat Inc, Englewood NJ, www.meta-analysis.com).

Abbreviations

CI: Confidence interval; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

ACKNOWLEDGMENTS AND FUNDING

This research was supported by Provincial Research Project for Health Care of Cadres in Sichuan, China (Grant No. Chuan Gan Yan 2013-802).

CONFLICTS OF INTEREST

The authors declared no competing financial interest.

Authors’ contributions

Conception/Design: Ting Wang, Yu Long. Data analysis and statistical guidance: Yu Long, Qian Gao, Chengya Zhou. Manuscript writing: Ting Wang, Yu Long. Final approval of the manuscript: Ting Wang, Yu Long, Chengya Zhou, Qian Gao.

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