Thrombocytopenia and the outcomes of hepatectomy for hepatocellular carcinoma: a meta-analysis

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Research review

Thrombocytopenia and the outcomes of hepatectomy for hepatocellular carcinoma: a meta-analysis Zhaohui Zhang, MD,a,1 Yi Zhang, MD,a,1 Wei Wang, PhD,b Yunpeng Hua, PhD,a Linyun Liu, MD,a Shunli Shen, PhD,a,* and Baogang Peng, PhDa,** a b

Department of Hepatic Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Department of Medical Ultrasonics, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

article info

abstract

Article history:

Background: Recently, increasing studies have revealed the association of inflammatory

Received 21 March 2016

parameters, such as preoperative platelet count, and the prognosis of hepatocellular car-

Received in revised form

cinoma (HCC). However, the link between the platelet count and the prognosis of patients

19 September 2016

with HCC after hepatic resection is still controversial.

Accepted 2 November 2016

Methods: We searched PubMed, Web of Science, EMBASE, and CBM for relevant trials and

Available online 11 November 2016

analyzed outcomes with random-effects model. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated.

Keywords:

Results: In total, 31 studies, including a total of 10,730 patients, met our criteria. The results

Blood platelets

showed that thrombocytopenia in HCC patients was associated with poor overall survival

Hepatocellular carcinoma

(HR ¼ 1.47, 95% CI: 1.21-1.78), disease-free survival (HR ¼ 1.36, 95% CI: 1.08-1.72), and a high

Hepatectomy

risk of cancer recurrence (HR ¼ 1.41, 95% CI: 1.22-1.62), but a low risk of extrahepatic

Meta-analysis

metastasis (HR ¼ 0.55, 95% CI: 0.47-0.63). Conclusions: The meta-analysis revealed that preoperative platelet count could act as a significant biomarker in the prognosis of HCC, especially a platelet count of <100  103/mm3. Additional high-quality trials are needed, considering the low-quality studies analyzed. ª 2016 Elsevier Inc. All rights reserved.

Introduction Hepatocellular carcinoma (HCC) is the sixth most prevalent neoplasm and the third most frequent cause of cancer

mortality.1 There are various methods to treat HCC, such as partial hepatectomy, percutaneous ablation therapy, and transarterial chemoembolization (TACE). However, the prognosis is still poor with an overall 5-y survival rate of 5%-6%.2

Previous presentation at a meeting: no. * Corresponding author. Department of Hepatic Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. Tel.: 0086-13631484663; fax: 0086-020-87755766-8214. ** Corresponding author. Department of Hepatic Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. Tel.: 0086-13922276105; fax: 0086-020-87755766-8214. E-mail addresses: [email protected] (S. Shen), [email protected] (B. Peng). 1 Contributed equally. 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.11.002

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The poor prognosis is attributable to many reasons, such as liver cirrhosis,3 portal vein thrombosis,4 local or extrahepatic tumor recurrence,5 and so on. Consequently, it would be helpful if we can identify related predisposing risk factors to improve the prognosis and reduce the recurrence rate. Platelets (PLTs) are best known for their role in hemostasis because their major function is the formation of blood clots in the case of a vessel wall injury.6 Recently, increasing studies have revealed the association between PLTs and HCC.7-9 Buergy et al10 found that preoperative thrombocytosis was associated with a poor prognosis in many types of cancer, including lung cancer, pancreatic adenocarcinoma, gastric cancer, and HCC. However, some other studies predicted that preoperative thrombocytopenia adversely affected survival in HCC patients who underwent liver resection. Sasan Roayaie et al11 recruited 132 HCC patients with a single HCC 2 cm and found that a preoperative PLT count <150  103/mm3 was independently associated with poor survival (hazard ratio [HR] ¼ 2.37, P ¼ 0.026). In addition, Hironobu Amano et al12 revealed that the rate of HCC recurrence was significantly lower in patients whose preoperative PLT count was 105/ mm3; 76of those patients (66%) experienced a recurrence of HCC after hepatectomy, compared with the 31 patients (89%) whose PLT count was <105/mm3. We conducted this meta-analysis to reveal the effect of thrombocytopenia on survival and recurrence in HCC patients receiving partial hepatectomy.

Methods Search strategy We followed the proposed Meta-Analysis of Observational Studies in Epidemiology13 guidelines to report our metaanalysis because all eligible trials were observational studies. PubMed, Web of science, EMBASE, and CBM (SINOMED) were searched using the following terms: (1) platelet or platelet count or thrombocytosis or thrombocytopenia or PLT; (2) hepatic carcinoma or hepatoma or liver cancer or hepatic cancer or HCC or hepatocellular carcinoma; (3) random control trial, cohort studies, prospective studies, follow-up studies, and retrospective studies. In addition, we researched the reference lists of the articles retrieved.

Study selection The initial screening was performed by reviewing the titles or abstracts. The second screening included a full-text review. Our inclusion criteria were as follows: (1) patients under study were limited to HCC, and the treatment was limited to hepatectomy; (2) the relationship between PLT and HCC was studied; (3) the outcomes of interest were overall survival (OS), disease-free survival (DFS), cancer recurrence (CR), and extrahepatic metastasis; and (4) HRs with corresponding 95% confidence intervals (CIs) and relative risk (RR) with corresponding 95% CIs were reported. The exclusion criteria were as follows: (1) letters, case reports, meeting records, and review articles; (2) lacking the key information to calculate the RR or HR and their 95% CIs; (3) HCC patients received ablation

or TACE treatment before hepatectomy. All screening was independently performed by two investigators. Disagreements were generally resolved by discussion, and a third investigator was consulted in the case of impasse.

Data extraction Data extraction was performed using a standardized data collection form. Any reported HRs or RRs of the outcomes listed above were extracted. Items related to the study characteristics for each study were also extracted. Data were recorded as follows: first author, year of publication, region, study population, type of analysis, cut-off value, follow-up, and HR or RR with its 95% CI. Study selection and data extraction were fulfilled independently by two investigators. Any disagreements were resolved by discussion. Quality assessment was also conducted by two independent investigators using the standard NewcastleeOttawa scoring system, as displayed in Table 1.

Statistical analyses The meta-analysis was performed according to the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.43 Statistical analyses were performed using Review Manager 5 (available from http:// www.cochrane.org/) and Stata 13 (available from http://www. stata.com/stata13/). We used HRs with corresponding 95% CIs to summarize the outcomes. Meta-analyses were performed using random-effects models, depending on the absence or presence of significant heterogeneity. Heterogeneity was evaluated using the c2 test with significance set at P < 0.10; I2 values were used for the evaluation of statistical heterogeneity.44 If the test rejected the assumption of homogeneity, the random effects analysis was performed.45 Sensitivity analyses were performed by removing individual studies from the data set and analyzing the effects on the overall results to identify the sources of significant heterogeneity.46 The Egger regression test was used to evaluate potential publication bias.

Results Initially, 2006 articles were retrieved from PubMed, Web of Science, EMBASE, and CBM. Of these, most were excluded after the first screening, mainly because they were reviews, case reports, had only abstracts available, or were not relevant to this analysis. After a full-text review of 48 studies, 17 studies were excluded (patients received TACE or studies lacked some data or key information). Finally, 31 studies were included. A flow chart showing the study selection is presented in Figure 1. The characteristics of the 31 studies are presented in Table 1, and most studies were conducted in Asia (n ¼ 25), particularly in Japan (n ¼ 17). Among the 31 studies included, 19 reported OS, nine reported DFS, two reported extrahepatic metastasis, and 12 reported CR. The PLT cut-off values of those studies ranged from 50 to 150  103/mm3, and 22 studies had a PLT cut-off value of 100  103/mm3. For the results of OS, 14 studies were calculated by the multivariate analysis, and eight studies were calculated via univariate analysis.

Table 1 e Main characteristics of eligible studies. Year

Region

Design

Study population

Amano et al12

2011

Japan

P

151

Taketomi A et al14

1998

Japan

R

Hirohashi et al15

2001

Japan

R

Type of analysis

Cut-off line (103/mm3)

Adjusted HR/RR

Quality score

17

Multivariate

100

OS: 2.155 (1.232-3.774) DFS: 1.653 (1.025-2.667) CR: 1.352 (1.132-1.615)

+++++++

210

NA

Multivariate

150

OS: 1.61 (1.09-2.38)

+++++++

257

7

Univariate

50

OS: 1.730 (1.131-2.646)

+++++++

2006

Japan

R

198

21

Univariate

100

OS: 0.974 (0.730-1.300) DFS: 1.137 (0.642-2.014)

+++++++

Hashimoto et al17

2004

Japan

R

149

3

Multivariate

120

OS: 1.65 (1.03-2.66) DFS: 2.10 (1.30-3.39)

+++++++

Masahiro Kobayashi et al18 Tseng et al19

2009

Japan

R

199

NA

Multivariate

100

DFS: 1.47 (1.03-2.12)

+++++++

2010

Taiwan

R

88

4

Multivariate/univariate

100

OS: 2.22 (1.19-4.17)/2.597 (1.366-4.973)

++++++++

2011

America

R

231

10

Univariate

150

OS: 0.826 (0.710-0.961)

++++++

Tsuyoshi Kobayashi et al

2011

Japan

P

266

9

Multivariate

100

OS: 2.7 (1.24-5.88) DFS: 1.476 (1.016-2.142)

++++++++

Roayaie et al11

2012

America

P

132

3

Multivariate

100

OS: 2.37 (1.07-5.24) CR: 2.963 (1.196-7.342)

++++++++

Zhao et al22

2012

China

R

162

1

Univariate

100

OS:0.658 (0.511-0.847)

++++

Miyatake et al23

2011

Japan

R

338

NA

Multivariate/univariate

100

OS: 1.35 (0.93-1.96)/1.72 (1.23-2.41) CR: 1.34 (1.03-1.74)

++++++

Giannini et al24

2013

Italy

R

152

NA

Univariate

100

OS: 1.067 (0.368-3.333)

+++++++

Lim et al25

2014

France

R

149

NA

Multivariate

150

OS: 5.039 (1.477-17.193)

++++++

Morimoto et al26

2014

Japan

R

803

2

Univariate

100

ER: 0.568 (0.428-0.754)

++++++

Nojiri et al

2014

Japan

R

292

NA

Multivariate

100

OS: 1.331 (0.542-3.270)

+++++++

Ochiai T et al28

2014

Japan

R

284

NA

Univariate

110

OS: 0.79 (0.46-1.35) DFS:0.71 (0.49-1.02)

++++++++

Lee et al29

2015

Taiwan

R

2753

5

Multivariate

118

ER: 0.54 (0.43-0.607)

++++++

Qing Pang et al30

2015

China

R

172

3.8

Multivariate

148

CR:1.79 (1.10-2.90)

++++++

Su et al31

2015

Taiwan

R

188

5.8

Multivariate

100

OS: 2.198 (1.274-3.793) CR: 1.208 (0.783-1.866)

++++++++

Santi et al32

2010

Italy

R

649

3.2

Multivariate

100

OS: 1.32 (1.04-1.67)

++++++++

Wong et al33

2013

Taiwan

R

82

NA

Univariate

100

DFS: 1.24 (0.64-2.42)

++++

Wu et al34

2015

China

R

86

NA

Multivariate

100

OS: 3.93 (1.82-8.51)

++++++++

2014

Japan

R

51

3.3-3.5

Univariate

100

CR: 0.80 (0.41-1.57)

++++++++

Kaibori et al

2013

Japan

R

74

12.5

Univariate

150

CR:6.06 (1.11-33.33)

++++++

Hagihara et al37

2011

Japan

R

182

3.7

Univariate

100

CR: 1.26 (0.85-1.86)

++++++++

Nonaka et al38

2010

Japan

R

64

1

Univariate

100

CR: 1.87 (0.62-5.68)

++++

Sasaki et al

16

Maithel et al20 21

27

Saito et al35 36

Follow-up (y)

101

(continued)

zhang et al  thrombocytopenia and the prognosis of hcc

Studies

102

++++++ 100 150 2097 R

NA

Multivariate

OS: 1.15 (0.89-1.49) OS: 1.18 (0.77-1.83)

++++

++++++ CR: 1.44 (0.93-2.23)

100 Univariate

CR: 2.00 (0.32-12.51)

100 Univariate

20 R

2.1

84 R

2.6

100 Multivariate 167 R

3.1

Study population Design

Follow-up (y)

Cut-off line (103/mm3)

DFS: 1.193 (1.154-3.179) CR: 2.46 (1.15-5.28)

++++++

Overall survival

Type of analysis

Adjusted HR/RR

Quality score

j o u r n a l o f s u r g i c a l r e s e a r c h  a p r i l 2 0 1 7 ( 2 1 0 ) 9 9 e1 0 7

Figure 2 shows that preoperative thrombocytopenia predicted a worse outcome for OS with a pooled HR of 1.47 (95% CI: 1.211.78, P < 0.001). Significant heterogeneity was observed (P < 0.001 and I2 ¼ 78.6%). Further analyses using the randomeffects model yielded identical results. To analyze the heterogeneity, some subgroup analyses were conducted. When the analysis method was considered, we found that preoperative low PLT was an obvious prognostic marker of short OS with the combined HR of 1.65 (95% CI: 1.38-1.97, P < 0.001), and there was lower heterogeneity (P < 0.001 and I2 ¼ 44.8%) for multivariate analysis, whereas the heterogeneity still existed for univariate analysis (P < 0.001 and I2 ¼ 82.9%). When performing subgroup analysis by ethnicity, preoperative thrombocytopenia was a negative prognostic marker in Asian cases (HR ¼ 1.57, 95% CI: 1.22-2.03, I2 ¼ 78.4%), whereas there was no significance in Caucasian populations (HR ¼ 1.25, 95% CI: 0.941.66, I2 ¼ 75.1%). An obvious heterogeneity was observed. Furthermore, the Asian HCC patients with low preoperative PLT levels had a shorter survival than the Caucasian HCC patients after receiving hepatectomy. Considering different cut-off values, similar results were revealed for the cut-off value of 100  103/mm3 (HR ¼ 1.52, 95% CI: 1.19-1.93, I2 ¼ 77.6%), whereas there was no sense for the cut-off value of 150  103/mm3 (HR ¼ 1.49, 95% CI: 0.92-2.41, I2 ¼ 82.9%). An obvious heterogeneity was still observed (Table 2).

Disease-free survival As shown in Figure 3, preoperative thrombocytopenia predicted worse outcomes for DFS with the pooled HR of 1.36 (95% CI: 1.08-1.72, P < 0.001). Significant heterogeneity was observed for DFS (P < 0.001 and I2 ¼ 57.0%). However, subgroup analyses revealed that preoperative thrombocytopenia was a negative predictor for DFS by multivariate analysis (HR ¼ 1.58, 95% CI: 1.32-1.89), and there was no heterogeneity (P ¼ 0.639 and I2 ¼ 0.0%); there was no statistical significance by univariate analysis (HR ¼ 0.93, 95% CI: 0.64-1.34). Considering different cut-off values, preoperative thrombocytopenia was a negative prognostic marker when the cut-off value of 100  103/mm3 was used (HR ¼ 1.45, 95% CI: 1.22-1.73, I2 ¼ 0.00%; Table 2).

America 2015

Twelve studies reported CR outcomes. The heterogeneity results were P ¼ 0.319, I2 ¼ 12.8%. After analysis, the results were HR ¼ 1.41, 95% CI: 1.22-1.62, P < 0.001 (Fig. 4), which indicated that preoperative thrombocytopenia contributes to a high risk of CR. Similar results were found by subgroup analysis (Table 2). In addition, we found that the Caucasians (HR ¼ 1.37, 95% CI: 1.22-1.54) with low preoperative PLT levels had an obviously increased risk of recurrence compared with Asians (HR ¼ 2.96, 95% CI: 1.19-7.34) after receiving hepatectomy.

Venkat et al

42

2000 Ikeda et al41

Japan

2007 Jeong et al40

Japan

2009 Kang et al39

Korea

Year Table 1 e (continued )

Studies

Region

Cancer recurrence

Extrahepatic metastasis Two studies reported extrahepatic metastasis outcomes. The heterogeneity results were P ¼ 0.765, I2 ¼ 0.00%. After analysis,

zhang et al  thrombocytopenia and the prognosis of hcc

Fig. 1 e Flow diagram of search strategy and study selection. (Color version of figure is available online.) the results were HR ¼ 0.55, 95% CI: 0.47-0.63, P < 0.05, which indicated that preoperative thrombocytopenia contributes to a low risk of extrahepatic metastasis (Fig. 5).

Publication bias The Egger’s linear regression test and the Begg test were performed to assess publication bias. As presented in Table 2, there was no obvious publication bias for the outcomes of DFS and CR (P > 0.05), but there was some indication of publication bias for OS (P < 0.05) and its subgroup analysis.

Discussion In 1964, Levin and Conley47 initially revealed the association between PLTs and cancer. They described that 38% of patients with a high PLT count had an unrecognized primary cancer. From then on, PLTs have been taken as prelude for various types of cancers.48,49 However, the link between PLTs and the prognosis of patients with HCC receiving hepatic resection is still controversial. This meta-analysis provided evidence that preoperative thrombocytopenia significantly predicted shorter postoperative survival for OS and DFS. However, obvious heterogeneity was observed. By subgroup analysis, we found similar results with lower heterogeneity by a multivariate analysis with a cut-off value of 100  103/mm3, and these subgroups might be potential sources of heterogeneity, rather than the ethnicity. In other words, HCC patients whose preoperative PLT

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Fig. 2 e Forest plot and meta-analysis of OS. (Color version of figure is available online.)

count <100  103/mm3 are liable to have a poor OS and DFS after receiving partial hepatectomy. A recent meta-analysis conducted by Pang Q et al50 showed similar findings, whereas the meta-analysis did not include the subgroup analysis or analyze the sources of heterogeneity for patients with HCC receiving hepatic resection. The results are contrary to many other solid tumors. For instance, a meta-analysis conducted by GU et al51 found that a PLT level increase might be a negative prognosis in patients with renal cell carcinoma. There may be some reasons for this. Thrombocytopenia was independently associated with hepatic carcinogenesis in patients with chronic hepatitis B virus or hepatitis C virus infection.52,53 In addition, a low PLT level generally occurs in cirrhotic patients because of portal hypertension, which has been previously shown to have a significant impact on survival for HCC patients after hepatic resection.54 Many studies have shown that the risk of complications and morbidity will increase after operation if the PLT level was low. On the basis of analyzing the results of 202 patients with HCC who underwent hepatectomy, Kubo et al55 thought that PLT, as a predictor of multicentric HCC, had a strong relationship with the severity of active hepatitis and hepatic fibrosis.50 As for the CR, preoperative thrombocytopenia contributes to a high risk of CR. A recent study indicated that PLTs might be a useful marker of portal vein invasion.56 In addition, a lower PLT count was found to be significantly associated with liver cirrhosis, hyperbilirubinemia, bleeding, and hepatic failure.57 All these factors contribute significantly to CR in HCC,57,58 which may help to explain the mechanism. We analyzed not only local recurrence but also extrahepatic metastasis. Our results were surprising in that preoperative

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Table 2 e Meta-analysis results. Outcomes OS

Variables

Number of study

Pooled HR

95% CI

P value

Heterogeneity I2 (%)

P value

Egger test (P value)

Begg test (P value)

All

19

1.47

1.21-1.78

<0.001

78.60

<0.001

<0.001

0.026

Analysis method Univariable

8

1.12

0.83-1.51

<0.001

82.90

<0.001

0.158

0.322

Multivariable

14

1.65

1.38-1.97

0.036

44.80

0.036

<0.001

0.007

100(103/mm3)

14

1.52

1.19-1.93

0.001

77.60

<0.001

0.016

0.208

150(103/mm3)

5

1.49

0.92-2.41

0.106

82.90

<0.001

NA

Asian

13

1.57

1.22-2.03

0.016

78.40

<0.001

0.003

Caucasian

6

1.25

0.94-1.66

0.246

75.10

<0.001

9

1.36

1.08-1.72

0.01

57.00

0.017

0.524

Univariable

3

0.93

0.64-1.34

0.681

35.70

0.211

NA

NA

Multivariable

5

1.58

1.32-1.89

<0.001

0.00

0.639

NA

NA

6

1.45

1.22-1.73

<0.001

0.00

0.818

0.473

0.543

12

1.41

1.22-1.62

<0.001

12.80

0.319

0.088

0.055

Cut-off values

NA

Ethnicity

DFS

All

NA

0.02 NA 0.917

Analysis method

Cut-off values 100(103/mm3) CR

All Analysis method Univariable

8

1.4

1.11-1.76

0.005

21.30

0.26

0.31

0.245

Multivariable

4

1.44

1.17-1.76

<0.001

18.50

0.298

NA

NA

10

1.36

1.21-1.53

<0.001

0.00

0.479

0.183

0.138

0.102

Cut-off values 100(103/mm3) Ethnicity Asian

11

1.37

1.22-1.54

<0.001

0.00

0.449

0.184

Caucasian

1

2.96

1.19-7.34

NA

NA

NA

NA

thrombocytopenia contributed to a low risk of extrahepatic metastasis. This had been proven in some in vitro and in vivo experiments. Carr BI et al59 reported that PLTs could stimulate the growth and invasion of several HCC cell lines in vitro. In addition, Y Yu et al60 found that the adhesion of human hepatoma cells (MHCC97) to the extracellular matrix protein was significantly enhanced by PLTs, and this may be mediated by PLT P-selectin and glycoprotein IIb-IIIa. In an in vivo experiment, Mitsuru Futakuchi et al61 revealed that aspirin had the potential to inhibit lung metastasis in rat HCC. However, the mechanism is still unclear. Many explanations have been proposed. First, through adding some angiogenic and tumor growth factors such as vascular endothelial growth factor, platelet-derived growth factor, P-selectin, and thrombospondin 1, PLTs might have accelerated the growth of the tumor,62,63 and this can induce the tumor celleinduced PLT aggregation.64 Second, PLTs protect circulating tumor cells from detection or attack by the immune system by facilitating cancer cell adhesion to the vascular endothelium through the formation of tumor thrombi and by interacting with tumor cells through PLT ligands.51,65 Third, PLTs cause the host’s response to growth factors to be increased by the tumor, which may directly increase the metastatic risk and worsen prognosis.51,66

NA

Based on the previously mentioned analysis, PLTs play an important role in cancer metastasis, and it appears to have an inverse relationship with PLT count compared with intrahepatic recurrence. It is hard to verify, but we speculate a few reasons. The characteristics of HCC are frequent local recurrence but relatively fewer systemic metastasis than other human cancers.67,68 In addition, we found that 25 of 31 retrieved papers were conducted in Asia, and most of the HCC patients had viral hepatitis and cirrhosis. This results in a high risk of portal vein tumor thrombosis, which is a major cause of intrahepatic recurrence.69 Moreover, the relatively low incidence of extrahepatic metastasis of HCC is, at least in part, attributable to cirrhosis-related thrombocytopenia. It is an interesting question whether cirrhosis-related thrombocytopenia could decrease the risk of metastasis in other human cancers. More research is needed on this topic. And this may also explain why the Caucasians with a low preoperative PLT had an obviously increased risk of recurrence and higher survival than the Asians after receiving hepatectomy for HCC. This analysis also has some limitations. First, significant heterogeneity was observed in some analyses. The presence of heterogeneity may be because of many factors, including study design, patients’ baseline characteristics, cut-off values, and so on. In addition, the extracted HRs of these studies

zhang et al  thrombocytopenia and the prognosis of hcc

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Fig. 5 e Forest plot and meta-analysis of extrahepatic metastasis. (Color version of figure is available online.)

Fig. 3 e Forest plot and meta-analysis of DFS. (Color version of figure is available online.)

might also have resulted in heterogeneity. Some studies (n ¼ 17) directly provided HRs; some studies (n ¼ 3) replaced it with RR, and one study had been conducted according to the

methods of Tierney et al.70 Finally, the conclusions of this meta-analysis are certainly limited by the design of the studies included because observational studies are considered to be relatively low-quality studies compared with randomized controlled trials.

Conclusions Our meta-analysis of observational studies suggests that preoperative thrombocytopenia is a negative predictor of OS, DFS, and the risk of CR in HCC patients receiving partial hepatectomy, particularly with a PLT count <100  103/mm3. However, these patients had an increased risk of extrahepatic metastasis. Further investigations are needed to examine whether there is any clinical benefit of the long-term use of antiplatelet therapy or PLT transfusions in the prevention of metastasis.

Acknowledgment Authors’ contributions: Z.Z. and S.S. contributed to the conception and design of the study, data analysis and interpretation, and writing the article. Y.H. and L.L. took responsibility for study selection and data extraction, B.P. contributed to the critical revision of the article. Y.Z. provided consultation on statistical analyzing methods and W.W. corrected grammar misuses and revised terminology jargons. Sponsored by Young Teacher Training Program (Grant number: 15ykpy15) and Natural Science Foundation of Guangdong Province (Grant number: 2014A030313108).

Disclosure

Fig. 4 e Forest plot and meta-analysis of CR. (Color version of figure is available online.)

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. The authors declare that they have no conflicts of interest.

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