Clinica Chimica Acta 475 (2017) 178–187

Contents lists available at ScienceDirect

Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/cca

C-reactive protein is a predictor of prognosis in renal cell carcinoma patients MARK

receiving tyrosine kinase inhibitors: A meta-analysis
Zhun Wang, Shuanghe Peng, Aixiang Wang, Hui Xie, Linpei Guo, Ning Jiang⁎, Yuanjie Niu⁎
Department of Urology, Tianjin Institute of Urology, The second Hospital of Tianjin Medical University, Tianjin 300211, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: The prognostic value of C-reactive protein (CRP) in metastatic renal cell carcinoma (RCC) patients
Metastatic renal cell carcinoma receiving tyrosine kinase inhibitors (TKIs) has been investigated in previous studies; however, the results remain
C-reactive protein inconclusive. This study investigated the prognostic value of pretreatment CRP in patients with metastatic RCC
Prognosis treated with TKIs.
Meta-analysis
Methods: PubMed, Embase, Web of Science, and Cochrane databases were searched for studies investigating the
relationships between pretreatment CRP and prognosis in patients with metastatic RCC. Hazard ratios (HRs) for
overall survival (OS) and progression-free survival (PFS) were extracted from eligible studies. Heterogeneity was
assessed using the I2 value. The fixed-effects model was used if there was no evidence of heterogeneity;
otherwise, the random-effects model was used. Publication bias was evaluated using Begg's funnel plots and
Egger's regression test.
Results: A total of 1199 patients from nine studies were included in the analysis. The results showed that an
elevated CRP level was an effective prognostic marker of both OS (pooled HR = 2.87, 95% confidence interval
[CI]: 2.34–3.54, p < 0.001) and PFS (pooled HR = 2.39, 95% CI: 1.75–3.26, p < 0.001). Subgroup analysis
revealed that an elevated CRP level significantly predicted poor OS and PFS in studies conducted in Japan (OS,
pooled HR = 3.03, 95% CI: 2.29–4.01, p < 0.001; PFS, pooled HR = 3.6, 95% CI: 1.62–8.0, p = 0.002), and in
cut-off value of CRP < 0.8 (OS, pooled HR = 2.93, 95% CI: 2.21–3.88, p < 0.001; PFS, pooled HR = 2.57, 95%
CI: 1.82–3.65, p < 0.001).
Conclusions: This study suggests that an elevated CRP level is correlated with poor prognosis in patients with
metastatic RCC receiving TKIs treatment.

1. Introduction
Renal cell carcinoma (RCC) is a common genitourinary malignancy
[1]. Nearly half of patients with RCC eventually progress to metastatic
disease, and the survival rate of these patients remains poor [2,3]. The
treatment of metastatic renal cell carcinoma was revolutionized with
the advent of tyrosine-kinase inhibitors (TKIs) in the past few decades.
Several agents targeting the vascular endothelial growth factor pathway
(sunitinib, sorafenib, pazopanib, and axitinib) were approved for first-
line or later-line use in the treatment of patients with metastatic RCC
[4–6]. The TKIs have consistently prolonged progression-free survival
(PFS) and overall survival (OS) among patients with metastatic RCC
[7]. However, these agents have provoked significant changes in the
management of RCC, and new predictive and prognostic clinical mar-
kers are required.
The prognostic value of inflammatory factors is concerning be-
cause of the association between inflammation and cancer develop-
ment [8,9]. C-reactive protein (CRP), a non-specific inflammatory
acute-phase protein, is elevated in the setting of systemic infections,
trauma, and malignancies [10]. Moreover, CRP has been identified as
an independent prognostic factor in several cancers [11–15]. Previous
reports have shown that an elevated CRP level predicts poor survival
of patients with metastatic RCC [16,17]. However, the association
between the CRP level and treatment outcome in patients with me-
tastatic RCC receiving TKIs has not been previously reviewed. We
conducted a systematic review and meta-analysis to assess the pre-

⁎
Corresponding authors at: Department of Urology, Tianjin Institute of Urology, The second Hospital of Tianjin Medical University, No.23, Pingjiang Road, Hexi District, Tianjin
300211, China.
E-mail addresses: jnbear@126.com (N. Jiang), yuanjieniu2014@163.com (Y. Niu).

http://dx.doi.org/10.1016/j.cca.2017.10.021
Received 19 September 2017; Received in revised form 20 October 2017; Accepted 22 October 2017
0009-8981/ © 2017 Published by Elsevier B.V.
Z. Wang et al.
dictive value of pretreatment CRP level in patients with metastatic
RCC receiving TKIs.
2. Materials and methods
2.1. Search strategy and selection criteria
This meta-analysis was performed using a predefined protocol in
accordance with PRISMA [18]. PubMed, Embase, Web of Science, and
the Cochrane electronic databases were searched for studies published
before September 9, 2017. The computer-based searches combined
terms related to “renal cell carcinoma,” “renal cell cancer,” “renal cell
adenocarcinoma,” or “kidney tumor”; as well as “C-reactive protein” or
“CRP”; and “prognosis,” “survival,” or “outcome” in humans. The lan-
guage of publication was restricted to English. Two reviewers (WZ and
PSH) independently screened the titles and abstracts of all initially
identified studies according to the selection criteria. Full-text articles of
studies that met all selection criteria were retrieved. The eligible studies
were required to meet the follow criteria: (1) retrospective studies on
the value of CRP in predicting prognosis in patients with metastatic
179
Clinica Chimica Acta 475 (2017) 178–187
Fig. 1. Flow diagram of the study selection process.
RCC; (2) patients who received TKIs therapy for metastatic RCC; (3)
hazard ratios (HRs) and 95% confidence intervals (95% CIs) for overall
survival or progression-free survival analysis reported in text or able to
be computed from given data; and (4) pretreatment CRP measured
before administering TKIs. When multiple reports describing the same
population were published, the most recent or most complete report
was used. The following were excluded: meeting abstracts, reviews,
case reports or comment letters; laboratory studies; animal studies;
duplicate publications; or studies published in a language other than
English.
2.2. Data extraction and quality
Two authors (ZW and SHP) independently extracted data and a
third author (AXW) was called to reach a consensus in the case of any
discrepancies. A predesigned data extraction form was used obtain re-
levant information. The data extracted from the eligible studies in-
cluded the following items: first author, year of publication, country of
origin, number of patients, histopathological information, cutoff value,
number of elevated CRP expressions, HR for survival (OS and/or PFS),
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

and follow-up time. For articles that only provided survival data in a
NOS

6
7

6
7
7
6
5
6
6
Kaplan-Meier curve, software designed by Jayne F. Tierney and
Matthew R. Sydes was used to digitize and extract the HR and its 95%
CI [19].
Survival
analysis

PFS,OS

PFS,OS

PFS,OS
PFS
2.3. Statistical analysis

OS
OS
OS
OS
OS
Data were analyzed using Stata SE12.0 (Stata Corp LP, College

> 0.33 mg/dl

> 0.3 mg/dl
> 0.5 mg/dl

> 1.7 mg/dl

> 0.3 mg/dl

> 0.5 mg/dl

≥ 0.8 mg/dl

≥ 0.8 mg/dl
Station, TX, USA). The hazard ratio (HR) with a 95% CI was selected as
CRP cut-off

> 1 mg/dl
the effect to measure prognosis outcomes. Interstudy heterogeneity was
value

evaluated using the chi-square test and I2 statistic

(100% × [(Q − df) / Q]) [20,21]; the value of Pheterogeneity < 0.1 and
I2 > 50% represents significant heterogeneity. A fixed-effects model
was used when the value of Pheterogeneity > 0.1 and I2 < 50%; other-
CRP(+) No.of

wise, a random-effects model was applied. Subgroup analysis was

131(65.5%)

187(69.0%)

49(55.68%)
patients(%)

28(68.3%)

73(52.1%)

44(35.5%)

performed for OS and PFS analysis. Begg's funnel plot and Egger's linear
32(63%)

33(50%)
65(35.1)

regression tests evaluated the potential for publication bias. Two-tailed

value of p < 0.05 was considered statistically significant.

3. Results
NA: not available. ccRCC: clear cell renal cell carcinoma; CRP: C-reactive protein; OS: overall survival; PFS: progression-free survival. NOS: Newcastle-Ottawa Scale score.
Median follow up

3.1. Features of included studies

6(1.1–116.2)
20(1 − 123)
15.6(1–57)

13.4(1–38)
7(1 −32)

19(2–64)
(months)

The workflow chart for this study is shown in Fig. 1. A total of 325
34.56
NA

potentially relevant studies were identified through systematic litera-

67

ture searches. Overall, 93 duplicate articles were removed. After

Unknown

screening titles and abstracts, 212 articles were excluded, including

reviews, letters, meeting abstracts, laboratory studies, and other articles
36

16

1
–

irrelevant to our study. After assessing the full text of the remaining
non-ccRCC

articles, 11 additional articles were excluded. Finally, 9 retrospective

Tumor Histology

studies [22–30] were included in the following meta-analysis.

NA

22
11
40
10
26

14

Summary characteristics of these studies are shown in Table 1. The

0

nine selected studies were published between 2012 and 2017. The
ccRCC

200

231

159

110

sample size ranged from 41 to 271 patients, and a total of 1199 patients
NA

62
93

40

81

were included. All trials were conducted in adult patients who received
66.81(30.8–81.35)
Median age(years)

TKIs. Six studies were conducted in Japan [22–25,28,29]. The three

other studies were conducted in Belgium [27], Sweden [30], and Ger-
64(36–80)
59(30–79)

67(31–93)
64(39–85)

66(21–78)
62(37–88)

63(37–81)

many [26]. The percentage of males included in each study ranged from
67.9% to 84.3%, and the median age of the study patients ranged from
NA

59 years to 67 years. The CRP cutoff value ranged from 0.3 to 1.7. For
the prognostic indicator of CRP level in patients with metastatic RCC
receiving TKIs, three articles reported both OS and PFS, five articles
Gender (male/

reported OS, and one article reported PFS.

female)

142/58

118/22
215/56

141/44
30/11

57/27

54/12

69/19
92/32

3.2. Survival outcome

A close relationship between cancer prognosis and CRP was de-

patients

tected in the included studies. Studies were adjusted for potential

No.of

confounders using the COX proportion hazard model.

200

140
271

185

124
41

84

66

88

OS and PFS were quantitatively synthesized. Fig. 2 shows the result

Germany
Belgium
Country

of the meta-analysis. OS values were available from eight studies

Sweden
Japan

Japan
Japan
Japan
Japan

Japan

[22,24–30] on metastatic RCC. Elevated CRP level was significantly

associated with poor OS (HR = 2.87, 95% CI: 2.34–3.54, p < 0.001;
2008.12–2011.08
2005.01–2012.10

2008.04–2013.09
2008.05–2014.04
2011.04–2014.12

2012.08–2015.09

I2 = 12%, Pheterogeneity = 0.337, Table 2, Fig. 2A), which meant that

patients with a higher CRP had a greater mortality risk than those with
2005–2012
2007–2011

2013–2014
Main characteristics of included studies.

a low CRP. Four studies [22,23,27,30] evaluated PFS outcome. Pooled

Duration

results favored the patients with low CRP (HR = 2.39, 95% CI:
1.75–3.26, p < 0.001; I2 = 23%, Pheterogeneity = 0.237, Table 2,
Fig. 2B).
2012
2014

2014
2014
2015
2015
2016
2016
2017
Year

Hideaki Miyake

Hideaki Miyake
Akira Miyazaki
Maria Stenman
Beuselinck

Steffen Rausch
Jun Teishima
Tetsuo Fujita

Kosuke Ueda
Authors

Benoit
Table 1

180
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

Fig. 2. Forest plot HR for the correlation between CRP level and OS (A) or PFS (B) in patients with metastatic RCC receiving TKIs treatment.

3.3. Subgroup analysis
Subgroup analysis was performed according to the cut-off value of
CRP and location of study (Table 2). We stratified cutoff values into two
subgroups: ≥ 0.8 and < 0.8. Pooled HRs for survival outcome stratified
by the cutoff value found that CPR < 0.8 predicted worse OS
(HR = 2.93, 95% CI: 2.21–3.88, p < 0.001, Table 2, Fig. 3A) and PFS
(HR = 2.57, 95% CI: 1.82–3.65, p < 0.001, Table 2, Fig. 4A). Sub-
group analysis according to country of publication showed that ele-
vated CRP level predicted worse OS (HR = 3.03, 95% CI: 2.29–4.01,
p < 0.001, Fig. 3B) and PFS (HR = 3.6, 95%CI: 1.62–8.0, p = 0.002,
Table 2, Fig. 4B) in Japanese studies.

181
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

3.4. Publication bias

< 0.001

< 0.001
P Value

0.12

0.26
Begg's funnel plots and Egger's test were used to assess the pub-

0
lication bias in this meta-analysis. Funnel plots for meta-analysis of

1.85(0.86,3.98)

2.57(1.82,3.65)
2.35(1.53,3.63)

1.86(0.64,5.44)
Random effect elevated CRP and OS and PFS are shown in Fig. 5. Both Begg's funnel

3.6(1.62,8.0)
plot test (OS: p = 0.386, PFS: p = 0.308; Fig. 5) and Egger's test (OS:
p = 0.226, PFS: p = 0.999) verified that no obvious publication bias
exists.
< 0.001

< 0.001

< 0.001
P Value

3.5. Sensitivity analysis

0.002

0.089
A sensitivity analysis was performed to evaluate the stability of
2.39(1.75,3.26)

2.57(1.82,3.65)
2.22(1.75,3.26)

1.8(0.92,3.55) results and to reduce the effect of the individual studies on final con-
3.6(1.62,8.0)
Fixed effect
HR(95%CI)

clusions. The test suggested that for OS and PFS, the pooled result did
not tend to alter when an individual study was excluded (Fig. 6).

4. Discussion
I2(%)

23

62

60
0

The treatment of metastatic RCC has been revolutionized in the past

Pheterogeneity

few decades. TKIs are primarily anti-angiogenic agents for the treat-
ment of solid tumors [31]. Several agents (sunitinib, bevacizumab,
0.273

0.776
0.105

0.115
0.45

pazopanib, axitinib) were progressively approved for first-line or later-

line use in the treatment of patients with advanced RCC [4–6]. The
Chi-squared

survival of patients with metastatic RCC has significantly improved

from a median OS of approximately 12 months in the cytokines era
3.89

0.08
2.62

0.57
2.48

to > 26 months with first-line TKIs inhibitors [4,5,32]. However, these

molecular targeted agents lack new prognostic markers. In this meta-
analysis, we explored a favorable prognosis in patients with metastatic
studies

RCC who have a low CRP and use TKIs. An elevated CRP level was
No.of
PFS

found to be an independent predictor of a poor prognosis in patients

4

2
2

2
2

with metastatic RCC receiving TKIs therapy.

< 0.001

< 0.001
< 0.001

< 0.001
< 0.001
P Value

The relationship between inflammation and cancer development

has been widely studied [33]. In established cancers, increasing evi-
dence exists of the role that local immune response and systemic in-
2.84(2.26,3.56)

2.98(2.26,3.56)
2.55(1.67,3.89)

2.86(2.03,4.03)
2.73(1.88,3.95)
Random effect

flammation have in the progression of tumors and survival of patients

with cancer [34]. Cancer-related inflammation has been suggested to
represent the seventh hallmark of cancer [35,36]. The inflammation
response is represented by the serum levels of white blood cells, neu-
trophils, lymphocytes and platelets, CRP, and albumin [37].
Bold in the table means the result of pooled HR from a fixed effect model or a random effect model.
< 0.001

< 0.001
< 0.001

< 0.001
< 0.001
P Value

CRP is an acute-phase reactant that can increase by 1000-fold in the

setting of systemic infections, trauma, and malignancies [38]. CRP is a
Pooled HR(95%CI)

vital component of the innate immune system which is synthesized

2.87(2.34,3.54)

3.03(2.29,4.01)
2.63(1.98,3.67)

2.93(2.21,3.88)
2.81(2.07,3.82)

mainly in the liver. Many studies involve the use of CRP as a prognostic
Fixed effect

marker in cancer [11–15]. Previous studies have shown that an ele-

vated CRP level predicts poor survival in patients with localized and
metastatic RCC [39–41]. CRP is easy to measure, uses widely available
standardized assays, and has the potential to serve as a prognostic
I (%)

15.2
31.9

marker for the clinical management of renal cancer.

12

21
27
2

Many studies have reported the prognostic value of CRP level, but
CRP pooled HRs and 95%CIs in meta-analysis for OS and PFS.

Pheterogeneity

the results are inconsistent. We conducted the meta-analysis to explore

the prognostic value of CRP level for patients with metastatic RCC who
0.337

0.318

0.282
0.251
0.23

receive TKIs. Our analysis revealed that CRP level is predictive of

prognosis for these patients. The cut-off values differed among the
Chi-squared

studies; in each study it seems the CRP cutoff value was calculated to
acquire the most significant effect from which the final significance of
7.96

4.71
2.94

3.82
4.1

the pooled HR was created. In subgroup analysis, the prognostic value

of the CRP level for OS exhibited no significant difference in the cutoff
value subgroup and the research location subgroup. However, the ele-
studies

vated CRP level was significantly associated with poor PFS in the Japan
No.of
OS

subgroup and cutoff value (< 0.8) group. The number of eligible stu-
8

5
3

4
4

dies was relatively small; however, we can conclude that the pooled
< 0.8 mg/dl
≥ 0.8 mg/dl
Stratified

Non-Asia
analysis

Overall

Nation

Cutoff
Table 2

Asia

182
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

Fig. 3. Subgroup analysis of pooled overall survival based on a CRP cutoff value (A) and nationality (B).

183
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

Fig. 4. Subgroup analysis of pooled progression-free survival based on a CRP cutoff value (A) and nationality (B).

184
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

Fig. 5. Funnel plots based on overall survival (A) Begg's test (B) Egger's test; and progression-free survival (C) Begg's test (D) Egger's test).

estimate of available studies indicates that a higher CRP level is asso- Abbreviations
ciated with a poor prognosis; whether the CRP level can serve pro-
spectively as a clinical marker of prognosis will need further in- CPR C-reactive protein
vestigation. To our knowledge, the present study is the first meta- RCC renal cell carcinoma
analysis to investigate the relationship between CRP and metastatic TKIs tyrosine kinase inhibitors
renal cell carcinoma treated with TKIs. HRs Hazzard ratios
Other limitations should be acknowledged. First, all included stu- OS Overall survival
dies in this meta-analysis measured CRP level, but the cut-off values PFS progression-free survival
differed among the studies, which may potentially contribute to het- CI confidence interval
erogeneity. Therefore, a more unified standard should be defined in the ZW Zhun Wang
future. Second, the number of patients included in the most eligible Shuanghe Peng Shuanghe Peng
studies was relatively small. Therefore, large-scale studies are necessary AXW Aixiang Wang
to achieve more reliable results. Finally, research with positive results is YJN Yuanjie Niu
more likely to be submitted and published than work with negative HX Hui Xie
results, which could cause publication bias, although this bias was not LPG Linpei Guo
detected in the present analysis [42]. NJ Ning Jiang

5. Conclusions
In summary, our analysis of currently available clinical evidence
suggests that elevated CRP levels predicted a poor OS and PFS in pa-
tients with metastatic RCC receiving TKIs treatment. The CRP could
serve as an indicator of the efficacy of TKIs in the treatment of meta-
static renal cell carcinoma.
Acknowledgments
We thank all the clinical investigators of the selected studies and
patients involved in these studies.
Funding
This meta-analysis has been financially supported by the Natural
Science Foundation of China (No. 81472682 and No. 81572538).

185
Z. Wang et al. Clinica Chimica Acta 475 (2017) 178–187

Fig. 6. Sensitivity analysis in this meta-analysis.

(A) Sensitivity analysis for OS; (B) Sensitivity
analysis for PFS.

Author's contributions review, Can. J. Urol. 15 (2008) 3954–3966.

YJN conceived and designed the study. ZW, SHP, and AXW searched
databases and collected the data. HX, LPG, and NJ analyzed and in-
terpreted the data. ZW and SHP wrote the manuscript. All authors re-
viewed the final manuscript.
Conflicts of interests
No conflicts of interest exist for any authors.
References
[1] R. Siegel, D. Naishadham, A. Jemal, Cancer statistics, 2012, CA Cancer J. Clin. 62
(2012) 10–29.
[2] K. Gupta, J.D. Miller, J.Z. Li, M.W. Russell, C. Charbonneau, Epidemiologic and
socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature re-
view, Cancer Treat. Rev. 34 (2008) 193–205.
[3] U. Athar, T.C. Gentile, Treatment options for metastatic renal cell carcinoma: a
[4] R.J. Motzer, T.E. Hutson, P. Tomczak, M.D. Michaelson, R.M. Bukowski, O. Rixe,
et al., Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, N. Engl. J.
Med. 356 (2007) 115–124.
[5] C.N. Sternberg, I.D. Davis, J. Mardiak, C. Szczylik, E. Lee, J. Wagstaff, et al.,
Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a
randomized phase III trial, J. Clin. Oncol. 28 (2010) 1061–1068.
[6] B.I. Rini, B. Escudier, P. Tomczak, A. Kaprin, C. Szczylik, T.E. Hutson, et al.,
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell car-
cinoma (AXIS): a randomised phase 3 trial, Lancet 378 (2011) 1931–1939.
[7] B. Escudier, L. Albiges, G. Sonpavde, Optimal management of metastatic renal cell
carcinoma: current status, Drugs 73 (2013) 427–438.
[8] M. Kowalewska, R. Nowak, M. Chechlinska, Implications of cancer-associated sys-
temic inflammation for biomarker studies, Biochim. Biophys. Acta 1806 (2010)
163–171.
[9] K. Saito, K. Kihara, C-reactive protein as a biomarker for urological cancers, Nat.
Rev. Urol. 8 (2011) 659–666.
[10] J. Huang, Y. Baum, M. Alemozaffar, K. Ogan, W. Harris, O. Kucuk, et al., C-reactive
protein in urologic cancers, Mol. Asp. Med. 45 (2015) 28–36.
[11] Y. Ibuki, Y. Hamai, J. Hihara, M. Emi, J. Taomoto, T. Furukawa, et al., Role of
postoperative C-reactive protein levels in predicting prognosis after surgical treat-
ment of esophageal cancer, World J. Surg. 41 (2017) 1558–1565.
[12] F.M. Kong, F.F. Gao, J. Chen, R.X. Zheng, H.G. Liu, X.J. Li, et al., Elevated serum C-

186
Z. Wang et al.
reactive protein level predicts a poor prognosis for recurrent gastric cancer,
Oncotarget 7 (2016) 55765–55770.
[13] N. Shao, Q.L. Cai, High pretreatment serum C-reactive protein level predicts a poor
prognosis for combined small-cell lung cancer, Tumor Biol. 36 (2015) 8465–8470.
[14] A. Tibau, M. Ennis, P.J. Goodwin, Post-surgical highly sensitive C-reactive protein
and prognosis in early-stage breast cancer, Breast Cancer Res. Treat. 141 (2013)
485–493.
[15] T. Nozoe, T. Matsumata, M. Kitamura, K. Sugimachi, Significance of preoperative
elevation of serum C-reactive protein as an indicator for prognosis in colorectal
cancer, Am. J. Surg. 176 (1998) 335–338.
[16] J. Atzpodien, P. Royston, T. Wandert, M. Reitz, D.T. Grp, Metastatic renal carci-
noma comprehensive prognostic system, Br. J. Cancer 88 (2003) 348–353.
[17] A. Casamassima, M. Picciariello, M. Quaranta, R. Berardino, C. Ranieri, A. Paradiso,
et al., C-reactive protein: a biomarker of survival in patients with metastatic renal
cell carcinoma treated with subcutaneous interleukin-2 based immunotherapy, J.
Urol. 173 (2005) 52–55.
[18] A. Liberati, D.G. Altman, J. Tetzlaff, C. Mulrow, P.C. Gotzsche, J.P.A. Ioannidis,
et al., The PRISMA statement for reporting systematic reviews and meta-analyses of
studies that evaluate health care interventions: explanation and elaboration, PLoS
Med. 6 (2009).
[19] J.F. Tierney, L.A. Stewart, D. Ghersi, S. Burdett, M.R. Sydes, Practical methods for
incorporating summary time-to-event data into meta-analysis, Trials 8 (2007) 16.
[20] H.H. Handoll, Systematic reviews on rehabilitation interventions, Arch. Phys. Med.
Rehabil. 87 (2006) 875.
[21] J.P. Higgins, S.G. Thompson, J.J. Deeks, D.G. Altman, Measuring inconsistency in
meta-analyses, BMJ 327 (2003) 557–560.
[22] H. Miyake, K.I. Harada, S. Ozono, M. Fujisawa, Assessment of efficacy, safety, and
quality of life of 124 patients treated with Axitinib as second-line therapy for me-
tastatic renal-cell carcinoma: experience in real-world clinical practice in Japan,
Clin. Genitourin. Cancer 15 (2017) 122–128.
[23] T. Fujita, M. Iwamura, D. Ishii, K.I. Tabata, K. Matsumoto, K. Yoshida, et al., C-
reactive protein as a prognostic marker for advanced renal cell carcinoma treated
with sunitinib, Int. J. Urol. 19 (2012) 908–913.
[24] K. Ueda, S. Suekane, K. Nishihara, N. Ogasawara, H. Kurose, S. Hayashi, et al.,
Duration of first-line treatment with molecular targeted-therapy is a prognostic
factor in metastatic renal cell carcinoma, Anticancer Res. 35 (2015) 3415–3421.
[25] H. Miyake, A. Miyazaki, S. Imai, K. Harada, M. Fujisawa, Early tumor shrinkage
under treatment with first-line tyrosine kinase inhibitors as a predictor of overall
survival in patients with metastatic renal cell carcinoma: a retrospective multi-in-
stitutional study in Japan, Target. Oncol. 11 (2016) 175–182.
[26] S. Rausch, S. Kruck, K. Walter, A. Stenzl, J. Bedke, Metastasectomy for metastatic
renal cell carcinoma in the era of modern systemic treatment: C-reactive protein is
an independent predictor of overall survival, Int. J. Urol. 23 (2016) 916–921.
[27] B. Beuselinck, Y.A. Vano, S. Oudard, P. Wolter, R. De Smet, L. Depoorter, et al.,
187
Clinica Chimica Acta 475 (2017) 178–187
Prognostic impact of baseline serum C-reactive protein in patients with metastatic
renal cell carcinoma (RCC) treated with sunitinib, BJU Int. 114 (2014) 81–89.
[28] A. Miyazaki, H. Miyake, K.I. Harada, T.A. Inoue, M. Fujisawa, Prognostic outcome
in patients treated with tyrosine kinase inhibitors as first-line molecular-targeted
therapy for metastatic renal cell carcinoma: experience in real-world clinical
practice in Japan, Mol. Clin. Oncol. 3 (2015) 601–606.
[29] J. Teishima, K. Kobatake, T. Hayashi, Y. Seno, K. Ikeda, H. Nagamatsu, et al.,
Prognostic significance of C-reactive protein in patients with intermediate-risk
metastatic renal cell carcinoma treated with molecular targeted therapy, Oncol.
Lett. 8 (2014) 881–885.
[30] M. Stenman, A. Laurell, M. Lindskog, Prognostic significance of serum albumin in
patients with metastatic renal cell carcinoma, Med. Oncol. 31 (2014) 841.
[31] C.G. Willett, Y. Boucher, E. di Tomaso, D.G. Duda, L.L. Munn, R.T. Tong, et al.,
Direct evidence that the VEGF-specific antibody bevacizumab has antivascular ef-
fects in human rectal cancer, Nat. Med. 10 (2004) 145–147.
[32] R.J. Motzer, T.E. Hutson, P. Tomczak, M.D. Michaelson, R.M. Bukowski, S. Oudard,
et al., Overall survival and updated results for Sunitinib compared with interferon
alfa in patients with metastatic renal cell carcinoma, J. Clin. Oncol. 27 (2009)
3584–3590.
[33] S.M. Crusz, F.R. Balkwill, Inflammation and cancer: advances and new agents, Nat.
Rev. Clin. Oncol. 12 (2015) 584–596.
[34] C.I. Diakos, K.A. Charles, D.C. McMillan, S.J. Clarke, Cancer-related inflammation
and treatment effectiveness, Lancet Oncol. 15 (2014) E493–E503.
[35] F. Colotta, P. Allavena, A. Sica, C. Garlanda, A. Mantovani, Cancer-related in-
flammation, the seventh hallmark of cancer: links to genetic instability,
Carcinogenesis 30 (2009) 1073–1081.
[36] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70.
[37] K. Maeda, M. Shibutani, H. Otani, H. Nagahara, T. Ikeya, Y. Iseki, et al.,
Inflammation-based factors and prognosis in patients with colorectal cancer, World
J. Gastroenterol. 7 (2015) 111–117.
[38] K.H. Allin, S.E. Bojesen, B.G. Nordestgaard, Baseline C-reactive protein is associated
with incident cancer and survival in patients with cancer, J. Clin. Oncol. 27 (2009)
2217–2224.
[39] Y. Komai, K. Saito, K. Sakai, S. Morimoto, Increased preoperative serum C-reactive
protein level predicts a poor prognosis in patients with localized renal cell carci-
noma, BJU Int. 99 (2007) 77–80.
[40] P.I. Karakiewicz, G.C. Hutterer, Q.D. Trinh, C. Jeldres, P. Perrotte, A. Gallina, et al.,
C-reactive protein is an informative predictor of renal cell carcinoma-specific
mortality - a European study of 313 patients, Cancer 110 (2007) 1241–1247.
[41] K. Saito, M. Tatokoro, Y. Fujii, Y. Iimura, F. Koga, S. Kawakami, et al., Impact of C-
reactive protein kinetics on survival of patients with metastatic renal cell carci-
noma, Eur. Urol. 55 (2009) 1145–1153.
[42] A.J. Sutton, F. Song, S.M. Gilbody, K.R. Abrams, Modelling publication bias in
meta-analysis: a review, Stat. Methods Med. Res. 9 (2000) 421–445.