Effect of Systemic Inflammation on Survival in Patients With Metastatic Renal Cell Carcinoma Receiving Second-line Molecular-targeted Therapy

doi:10.1016/j.clgc.2017.01.018

Clinical Genitourinary Cancer

Volume 15, Issue 4, August 2017, Pages 495-501

https://doi.org/10.1016/j.clgc.2017.01.018 Get rights and content

Abstract

Background

The role of systemic inflammatory markers, including C-reactive protein (CRP), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), in predicting survival for patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy (mTT) after first-line tyrosine kinase inhibitor failure remains unclear. Thus, we investigated the relationship between systemic inflammation and survival in such patients.

Patients and Methods

Sixty-three patients were evaluated. Progression-free survival (PFS) and overall survival (OS) after second-line mTT initiation were evaluated according to the inflammatory marker levels. In addition, the prognostic factors for survival were examined.

Results

The receiver operating characteristic curves for CRP, NLR, and PLR had areas under the curve of 0.779, 0.619, and 0.655, respectively; no significant differences were noted. The corresponding cutoff values were 0.48, 2.53, and 183. Patients with higher CRP (n = 40), NLR (n = 32), and PLR (n = 22) levels had significantly lower PFS and OS than those with lower CRP, NLR, and PLR levels. Multivariate analyses showed that CRP was the sole independent predictor for PFS and OS.

Conclusion

Systemic inflammation is associated with survival after second-line mTT. In particular, CRP was a strong independent predictive biomarker of prognosis.

Introduction

The current treatment strategy for metastatic renal cell carcinoma (mRCC) consists of molecular-targeted therapy (mTT) to improve and prolong patient survival.¹ To further improve treatment strategy and, consequently, patient survival, identifying the predictive factors or risk classifications is necessary.

The functional relationship between systemic inflammation and cancer is well recognized.2, 3 The tumor microenvironment, which is orchestrated by inflammatory cells, is an indispensable factor in the neoplastic process, fostering cell proliferation, survival, and migration.⁴ In RCC, an association between systemic inflammation and prognosis has been demonstrated. C-reactive protein (CRP) has been identified as an independent predictive biomarker for survival in patients with RCC with or without metastasis.5, 6, 7, 8, 9 Moreover, the neutrophil/lymphocyte ratio (NLR) has been identified as an effective predictor in patients with mRCC receiving mTT.10, 11 These relationships have been attributed to the mechanism by which RCC cells produce inflammatory cytokines, such as interleukin-6, inducing CRP, and neutrophils.12, 13, 14, 15 Furthermore, the platelet/lymphocyte ratio (PLR) has been identified as a predictive biomarker in patients with cancer, including RCC.16, 17, 18 Several platelet-derived cytokines related to tumor angiogenesis regulation, such as vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor, have been found to be elevated in patients with cancer.19, 20

In a recent retrospective largescale study, the neutrophil and platelet levels were independent predictive factors of the prognosis in patients with mRCC who had received second-line mTT after progression during first-line therapy.²¹ Therefore, we hypothesized that the NLR and/or PLR would also be associated with patient survival after second-line mTT. To the best of our knowledge, the effect of the NLR or PLR in predicting survival in the second-line setting remains unclear, although this has been demonstrated in first-line therapy.10, 18 Moreover, the association among systematic inflammatory markers, including CRP, NLR, and PLR, in the second-line setting is unknown.

Thus, we investigated the correlation among systemic inflammatory markers (CRP, NLR, and PLR) and the influence of these biomarkers in predicting the survival of patients with mRCC receiving second-line mTT after first-line tyrosine kinase inhibitor (TKI) failure.

Section snippets

Patient and Study Design

Of the 115 patients who had received second-line mTT at our department from January 2007 to August 2016, 52 were excluded. The reasons for exclusion were previous cytokine therapy (n = 23), previous dialysis therapy (n = 6), second-line mTT because of adverse events during first-line therapy (n = 11), mammalian target of rapamycin inhibitor (mTORi) as a first-line agent (n = 7), and missing data (n = 5). The remaining 63 patients were evaluated. The clinical and laboratory data were obtained

Patient Background

The patient characteristics are listed in Table 1. Of the 63 patients, 36 were ≥ 65 years old (57.1%), and 44 were men (69.8%). Clear cell carcinoma (CCC) was observed in 48 patients (76.2%), and non-CCC, including papillary RCC, CCC with spindle cells, Bellini duct carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma, and unknown, was observed in 5 (7.94%), 4 (6.35%), 1 (1.59%), 1 (1.59%), 1 (1.59%), and 3 (4.76%) patients, respectively. Previous nephrectomy had been

Discussion

A close relationship between systemic inflammation and prognosis in RCC has been recognized. Chronic systemic inflammation caused by CRP or neutrophils produced by cancer cells can affect the host's nutritional condition, resulting in a poor prognosis, by directly accelerating tumor growth and dissemination or impairing treatment tolerability.24, 25 Moreover, lymphocytes play a role in the host's immunity against cancer and are thought to possess an antitumor effect by inducing cell apoptosis,

Conclusion

Systemic inflammatory markers (specifically, CRP, NLR, and PLR) have prognostic value for PFS and OS in patients with mRCC receiving second-line mTT after first-line TKI failure. Furthermore, CRP was demonstrated to be a strong independent predictive biomarker. Patients with systemic inflammation have a poor prognosis despite second-line therapy initiation. Therefore, careful follow-up must be performed for such high-risk patients. In addition, these markers could be used to determine the best

Disclosure

T. Kondo has received honoraria from Pfizer, Bayer, and Novartis. The remaining authors declare that they have no competing interests.

Acknowledgments

We thank Nobuko Hata (Tokyo Women's Medical University) for secretarial support and Editage for English language editing.

References (29)

R. Figlin et al.
Novel agents and approaches for advanced renal cell carcinoma
J Urol
(2012)
F. Balkwill et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001)
A.J. Templeton et al.
Change in neutrophil-to-lymphocyte ratio in response to targeted therapy for metastatic renal cell carcinoma as a prognosticator and biomarker of efficacy
Eur Urol
(2016)
W.J. Jabs et al.
Expression of C-reactive protein by renal cell carcinomas and unaffected surrounding renal tissue
Kidney Int
(2005)
H.M. Pinedo et al.
Involvement of platelets in tumour angiogenesis?
Lancet
(1998)
J.J. Ko et al.
The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study
Lancet Oncol
(2015)
A. Mantovani et al.
Cancer-related inflammation
Nature
(2008)
L.M. Coussens et al.
Inflammation and cancer
Nature
(2002)
S. Steffens et al.
Validation of CRP as prognostic marker for renal cell carcinoma in a large series of patients
BMC Cancer
(2012)
K. Saito et al.
Impact of C-reactive protein kinetics on survival of patients with metastatic renal cell carcinoma
Eur Urol
(2009)

G.W. Lamb et al.

The relationship between the local and systemic inflammatory responses and survival in patients undergoing resection for localized renal cancer

BJU Int

(2008)

M. de Martino et al.

Validation of serum C-reactive protein (CRP) as an independent prognostic factor for disease-free survival in patients with localised renal cell carcinoma (RCC)

BJU Int

(2013)

B. Beuselinck et al.

Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib

BJU Int

(2014)

N. Na et al.

Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors

Oncotarget

(2016)

Cited by (20)

Predictive impact of an early change in serum C-reactive protein levels in nivolumab therapy for metastatic renal cell carcinoma
2020, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Serum C-reactive protein (CRP) is one of the most intensively studied inflammatory factors, and its level acts as a predictor of mRCC. The prognostic association of this factor with various therapies, including surgery [8–12], cytokine therapy [13,14], and molecular-targeted therapy [15–21], has been indicated. However, the amount of evidence regarding the predictive impact of CRP on survival after ICI therapy remains low.
To investigate the predictive impact of a change in serum C-reactive protein (CRP) levels during the early phase of nivolumab therapy for metastatic renal cell carcinoma (mRCC).
Seventy mRCC patients treated with nivolumab after molecular-targeted therapy failure were retrospectively evaluated. Based on the CRP change, patients were classified as (1) normal: if pretreatment levels were <1 mg/dl; (2) normalized: if pretreatment levels were ≥1.0 mg/dl and nadir levels within the initial three months of nivolumab therapy declined to <1.0 mg/dl; and (3) non-normalized: if pretreatment levels were ≥1 mg/dl and nadir levels remained ≥1.0 mg/dl. The predictive association between the CRP change and progression-free survival (PFS) and overall survival (OS) after nivolumab initiation was evaluated.
The PFS was significantly lower in the non-normalized group (n = 25, 35.7%) than in the normal (n = 29, 41.4%) (median: 2.33 vs. 6.28 months, P = 0.0009) and normalized (n = 16, 22.9%) (2.33 vs. 8.38 months, P = 0.0006) groups, while no differences were observed between normal and normalized groups (P = 0.610). The OS was significantly lower in the non-normalized group than in the normal (8.02 months vs. not reached, P < 0.0001) and normalized groups (8.02 vs. 26.0 months, P = 0.0047); further, the OS of the normalized group was lower than that of the normal group (P = 0.0454). Multivariate analyses showed that the CRP change was an independent factor for PFS (P = 0.0025) and OS (P = 0.0009).
The CRP change during the early phase of nivolumab therapy was significantly associated with mRCC patient survival and may thus be used for outcome prediction.
Platelet-to-lymphocyte ratio in advanced Cancer: Review and meta-analysis
2018, Clinica Chimica Acta
Citation Excerpt :
The full texts of the remaining 190 studies were retrieved for further assessment and 157 trials were excluded. Finally, 33 studies [17–49] were included in the meta-analysis work. A total of 8215 patients were eligible for assessment, and the clinical characteristics of the included researches were shown in Table 1.
Inflammation biomarkers have been introduced into clinical practice for risk-rating in treatment of patients with cancer. We aimed to confirm the prognostic role of platelet-to-lymphocyte ratio (PLR) as a powerful biomarker for patients with advanced cancer.
A systematic literature search was conducted through PubMed, Embase and Web of Science databases for studies on advanced tumors. Research articles that analyzed the PLR and hazard ratios (HR) in patients with overall survival (OS) or progression-free survival (PFS) data were involved. Two authors assessed the eligibility of trials and extracted data independently. Meta-analyses were performed with random-effect models. Data heterogeneity was calculated with the I² method.
Thirty-three eligible cohort studies including 8215 patients were further analyzed. Elevated PLR was associated with reduced OS (HR = 1.45, 95% CI, 1.31–1.61, p < 0.001) and PFS (HR = 1.73, 95% CI, 1.31–2.29, p < 0.001) in patients with advanced cancer. A extreme result was observed in a subgroup analysis in metastatic renal cancer with the worst OS (HR = 2.47, 95% CI, 1.32–4.62, p = .005) and PFS (HR = 3.89, 95% CI, 1.23–12.28, p = 0.021).
Patients with high pretreatment blood PLR level have poor OS and PFS. Further investigations are needed to explore the underlying mechanisms.
Prognostic Value of Baseline Serum C-Reactive Protein Level in Intermediate-Risk Group Patients With Metastatic Renal-Cell Carcinoma Treated by First-Line Vascular Endothelial Growth Factor–Targeted Therapy
2018, Clinical Genitourinary Cancer
Almost half of patients with metastatic renal-cell carcinoma (mRCC) are classified as intermediate risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. The aim of this study was to evaluate whether baseline C-reactive protein (CRP) levels predict overall survival (OS) in intermediate-risk group mRCC patients.
Data from 107 intermediate-risk group mRCC patients receiving first-line targeted therapy were retrospectively reviewed. We evaluated the correlation between baseline CRP levels as well as other indices and OS.
Of the 107 patients with intermediate-risk disease, 46 patients (43%) were classified as having elevated CRP levels. The elevation of pretreatment serum CRP levels was the independent prognostic factor of OS in patients with intermediate risk (hazard ratio, 4.609; P = .001). The 1- and 3-year survival rates of patients with intermediate–nonelevated CRP were 90.0% and 64.7% compared to the favorable-risk group, at 92.1% and 68.5%, respectively. In contrast, the 1- and 3-year survival rates of patients with intermediate–elevated CRP were 80.5% and 37.4% compared to the poor-risk group, at 65.2% and 24.2%, respectively.
Baseline CRP levels could divide mRCC patients in the intermediate-risk group into 2 prognostic subgroups.
Association Between Pretreatment Neutrophil-to-Lymphocyte Ratio and Outcome of Patients With Metastatic Renal-Cell Carcinoma Treated With Nivolumab
2018, Clinical Genitourinary Cancer
Biomarkers to guide treatment in metastatic renal-cell carcinoma (mRCC) are lacking. We aimed to investigate the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and outcome of patients with mRCC receiving nivolumab.
Through retrospective chart review, we identified 38 patients with mRCC treated with standard-of-care nivolumab between 2015 and 2016 at Winship Cancer Institute of Emory University. NLR was determined from complete blood count collected before starting treatment, and imaging was performed to assess progression. The NLR cutoff value of 5.5 was determined by log-rank test, and the univariate association with overall survival (OS) or progression-free survival (PFS) was assessed by the Cox proportional hazard model and Kaplan-Meier method.
The 38 patients had a median age of 69 years. The PFS and OS for all patients at 12 months was 54% and 69%, respectively. The median PFS was 2.6 months in the high NLR group but not reached in the low NLR group. Low NLR was strongly associated with increased PFS with hazard ratio of 0.20 (95% confidence interval, 0.07-0.64; P = .006). The median OS was 2.7 months in the high NLR group but not reached in the low NLR group. Low NLR was significantly associated with a prolonged OS with hazard ratio of 0.06 (95% confidence interval, 0.01-0.55; P = .012).
Pretreatment NLR < 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies.
Platelet-lymphocyte ratio acts as an independent predictor of prognosis in patients with renal cell carcinoma
2018, Clinica Chimica Acta
Citation Excerpt :
A total of 1528 patients were included in the meta-analysis and the sample size ranged from 26 to 484 patients. The median age of the study patients ranged from 56 to 69 y. Four studies were conducted in the Asian country, including China [22], Japan [11,14], and Korea [13]. The two other studies were conducted in Australia [12,20] and Turkey [21].
The prognostic value of plated-lymphocyte ratio (PLR) in multiple malignancies had been investigated in previous studies; however, its prognostic value in renal cell carcinoma (RCC) remains controversial. This study was performed to assess the prognostic value of preoperative PLR in RCC patients.
Literature was searched from PubMed, Embase, Web of Science and Cochrane database, which evaluated the relationships between preoperative PLR and prognosis in RCC patients. 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.
A total of 1528 patients from seven studies were included in the analysis. The pooled analysis showed that an elevated PLR was an effective prognostic marker of both OS (pooled HR = 2.10, 95%CI: 1.38–3.19, p = 0.001) and PFS (pooled HR = 3.45, 95%CI: 1.61–7.40, p = 0.001). Subgroup analysis revealed that a high PLR significantly predicted worse OS and PFS in Asian studies (OS, pooled HR = 2.72, 95%CI: 1.06–7.03, p = 0.038; PFS, pooled HR = 6.0, 95%CI: 3.12–11.54, p < 0.001), in metastatic RCC patients receiving mixed therapies (OS, pooled HR = 3.69, 95%CI: 1.93–11.42, p = 0.023; PFS, pooled HR = 6.05, 95%CI: 1.34–27.37, p = 0.019) and targeted therapy (OS, pooled HR = 1.59, 95%CI: 0.97–2.62, p = 0.067), in sample size >100 (OS, pooled HR = 1.83, 95%CI: 1.49–2.25, p < 0.001; PFS pooled HR = 6.05, 95%CI: 1.34–27.37, p < 0.019), and in cut-off value of PLR ≤ 195 (OS, pooled HR = 3.65, 95%CI: 1.06–12.60, p = 0.04; PFS pooled HR 4.46, 95%CI: 1.68–11.87, p = 0.003).
This study suggests that a high preoperative PLR is correlated with poor prognosis in RCC patients.
The impact of neutrophil-to-lymphocyte, platelet-to-lymphocyte and haemoglobin-to-platelet ratio on localised renal cell carcinoma oncologic outcomes
2019, Progres en Urologie
The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) are established markers of systemic inflammation. Moreover, anemia is a known adverse prognostic factor and reduced haemoglobin to platelet ratio (HPR) seems associate to poor outcomes in urothelial cancer. Aim of the current study was to explore the prognostic value of NLR, HPR and PLR in patients harboring localized RCC.
Materials and Methods 184 patients undergoing partial and radical nephrectomy for renal mass in a single hospital were retrospectively analyzed. Uni- and multivariate logistic regressions were performed to assess associations between various risk factors, including NLR, PLR and HPR and locally advanced disease (≤ pT2 vs. ≥ pT3) and tumor grade. Kaplan Meier curves and Cox regressions were constructed to assess the association of NLR, PLR and HPR to recurrence free survival (RFS), cancer specific survival (CSS) and overall survival (OS). To determine thresholds for variables, we considered the 75^th percentile of our distribution of values, which was computed at 3.45 for NLR, 189 for PLR and 0.48 for HPR. A two-sided P < 0.05 defined statistical significance.
Patients with an elevated NLR (> 3.45) were more likely to present with ≥ pT3 stage (p = 0.046). RFS was significantly different according to NLR value, with patients having an NLR > 3.45 experiencing significantly worst RFS (P = 0.019); similarly, an increased PLR was significantly associated to a reduced RFS (P = 0.012). Restricting the Cox regression to patients with locally advanced disease (≥ pT3), NLR was even more associated to recurrence (HR 3.22; 95%CI: 1.06–9.81, P = 0.039). Patients exhibiting an NLR > 3.45 (p = 0.03) or a PLR > 189 (P = 0.005) did have a significantly worse CSS, while a HPR < 0.48 did not predict CSS (P = 0.12) on Kaplan Meier curves. Finally, an increased NLR (P = 0.047), increased PLR (P = 0.0006) and decreased HPR (P = 0.05) were all associated to a poor overall survival on univariate analysis. On multivariate analysis, only HPR remained significantly predictive of OS (HR 0.077; 95%CI: 0.02–0.37, P = 0.001).
In this single-center study analyzing non-metastatic RCC, an increased NLR was significantly associated to a reduced RFS, CSS and OS on univariate analyses and to RFS on multivariate analysis. Larger prospective studies are needed to validate our findings.
4.
Le rapport neutrophile/lymphocyte (NLR) et le rapport plaquette/lymphocyte (PLR) sont des marqueurs établis de l’inflammation systémique. L’anémie est un facteur pronostique défavorable connu et une diminution du rapport hémoglobine/plaquettes (HPR) pourrait être associée à un moins bon pronostic dans le cancer rénal. Le but de cette étude était d’explorer la valeur pronostique des NLR, HPR et PLR chez les patients ayant un cancer à cellules rénales localisé.
Un total de 184 patients opérés d’une néphrectomie partielle ou radicale pour une tumeur rénale dans un seul centre hospitalier ont été analysés de manière rétrospective. Des régressions logistiques uni- et multivariées ont été réalisées pour évaluer les associations entre divers facteurs de risque, y compris le NLR, le PLR et le HPR et la maladie localement avancée (≤ pT2 vs ≥ pT3) et le grade tumoral. Les courbes de Kaplan Meier et des régressions de Cox ont été construites pour évaluer l’impact du NLR, du PLR et du HPR sur la survie sans récidive (SSR), la survie spécifique au cancer (SSC) et la survie globale (SG). Les seuils choisis pour les différents marqueurs correspondent au 75^e percentiles des distributions : ils ont été calculés à 3,45 pour le NLR, 189 pour le PLR et 0,48 pour le HPR. Un p < 0,05 a été considéré comme significatif.
Les patients avec un NLR > 3,45 étaient plus à risque de présenter un stade ≥ pT3 (p = 0,046). Un NLR > 3,45 et un PLR > 189 étaient associés avec une SSR diminuée (p = 0,019 et p = 0,012, respectifs). En limitant la régression de Cox aux patients atteints d’une maladie localement avancée (≥ pT3), le NLR élevé était associé à la récidive (HR 3,22 : IC 95 % : 1,06–9,81, p = 0,039). Les patients présentant un NLR > 3,45 (p = 0,03) ou un PLR > 189 (p = 0,0005) avait une SSC significativement réduite, alors que un HPR < 0,48 n’était pas associé à la SSC sur la curbe de Kaplan-Meier. En fin, un NLR augmenté (p = 0,047), un PLR augmenté (p = 0,0006) et un HPR réduit (p = 0,05) étaient associés à une réduction de SG en analyse univariée. Seulement l’HPR restait significativement prédictive d’une SG réduite en analyse multivariée (HR 0,077 : 95 %CI : 0,02–0,37, p = 0,001).
Dans cette étude monocentrique analysant le RCC non métastatique, une augmentation du NLR était significativement associée à réduction de la SSR, SSC et SG sur des analyses univariées et à SSR sur l’analyse multivariée. De plus amples études prospectives sont nécessaires pour valider nos résultats.
4.

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Original StudyEffect of Systemic Inflammation on Survival in Patients With Metastatic Renal Cell Carcinoma Receiving Second-line Molecular-targeted Therapy

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Patient and Study Design

Patient Background

Discussion

Conclusion

Disclosure

Acknowledgments

J Urol

Lancet

Eur Urol

Kidney Int

Lancet

Lancet Oncol

Cancer-related inflammation

Nature

Inflammation and cancer

Nature

Validation of CRP as prognostic marker for renal cell carcinoma in a large series of patients

BMC Cancer

Impact of C-reactive protein kinetics on survival of patients with metastatic renal cell carcinoma

Eur Urol

The relationship between the local and systemic inflammatory responses and survival in patients undergoing resection for localized renal cancer

BJU Int

Validation of serum C-reactive protein (CRP) as an independent prognostic factor for disease-free survival in patients with localised renal cell carcinoma (RCC)

BJU Int

Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib

BJU Int

Meta-analysis of the efficacy of the pretreatment neutrophil-to-lymphocyte ratio as a predictor of prognosis in renal carcinoma patients receiving tyrosine kinase inhibitors

Oncotarget

Original Study
Effect of Systemic Inflammation on Survival in Patients With Metastatic Renal Cell Carcinoma Receiving Second-line Molecular-targeted Therapy