Elsevier

European Urology

Volume 55, Issue 5, May 2009, Pages 1145-1154
European Urology

Kidney Cancer
Impact of C-Reactive Protein Kinetics on Survival of Patients with Metastatic Renal Cell Carcinoma

https://doi.org/10.1016/j.eururo.2008.10.012Get rights and content

Abstract

Background

Pretreatment C-reactive protein (CRP) level has been shown to be prognostic for metastatic renal cell carcinoma (mRCC).

Objectives

To demonstrate that CRP would be a biomarker for mRCC, we evaluated the impact of CRP kinetics on survival.

Design, setting, and participants

One hundred eight patients with mRCC were treated from 1994 to 2007 with a median follow-up period of 18 mo (interquartile range: 7–40 mo).

Intervention

All patients underwent multimodal therapeutic intervention.

Measurement

Patients were divided into three groups according to CRP kinetics. Patients whose pretreatment CRP levels were <5 mg/l, patients whose pretreatment CRP levels were >5 mg/l and normalized (<5 mg/l) at least one time during treatment, and patients whose pretreatment CRP levels were >5 mg/l and never normalized were assigned to nonelevated, normalized, and non-normalized CRP groups, respectively. The prognostic impact of CRP kinetics and the correlation between normalized CRP period and overall survival period were determined.

Results and limitations

In 61 of the 108 patients (56%), CRP levels were elevated at the diagnosis of mRCC. During treatment, CRP levels were normalized in 30 of 61 patients (49%), whereas CRP levels remained elevated in the remaining 31 patients. Overall survival rates were significantly different between nonelevated, normalized, and non-normalized CRP groups (p < 0.001) with 2-yr survival rates of 69%, 55%, and 4%, respectively. In multivariate analysis, CRP kinetics was an independent significant factor for overall survival. Normalized CRP period was significantly correlated with overall survival period in 78 patients who died of disease. Since this is a small retrospective study on patients within the past era of immunotherapy, larger confirmatory studies in the current era of targeted therapy are needed.

Conclusions

CRP can be a novel, widely available biomarker for patients with mRCC.

Introduction

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies [1] and is the fourth most common urogenital malignancy in Japan [2]. Approximately 30% of patients are diagnosed with metastases [3], and an additional 30% of patients develop metastases after radical nephrectomy with curative intent. The outcome of patients with metastatic RCC (mRCC) is poor, with a median survival time of 10 mo [4] and a 5-yr survival rate of <10%.

The management of metastatic RCC has progressed in the last decade. A survival advantage of debulking cytoreductive nephrectomy followed by immunotherapy in patients with metastatic RCC was validated in two prospective, randomized trials [5], [6]. Although immunotherapy consisting of recombinant interleukin (IL)-2 and recombinant interferon (IFN)-α has been considered standard treatment for patients with mRCC [7], [8], [9], the development of new molecular-targeted agents, such as sorafenib, sunitinib, and temsirolimus, would be the novel new standard therapy for these patients. Several prognostic factors for patients with mRCC have been identified to improve the selection of patients for the optimal management [4], [10], [11], [12], [13].

A remarkable association between systemic inflammatory response and the prognosis of patients with RCC has been demonstrated. C-reactive protein (CRP), an acute-phase protein, is a representative marker of systemic inflammatory response. The production of CRP in the liver is strongly induced by proinflammatory cytokines such as IL-1, tumor necrosis factor, and mostly IL-6 [14]. Experimental studies in RCC cell lines and expression studies in nephrectomized specimens showed that at least some renal tumors are actually able to produce IL-6 [15], [16]. Thus, RCC can induce systemic inflammatory response. Serum CRP level was also elevated in various disorders including infection, inflammatory arthritides [17], cardiovascular disease [18], and other malignancies [19], [20].

CRP has been one of the significant factors in predicting survival in patients with RCC. We and other investigators demonstrated that elevated CRP level predicts poorer survival of metastatic as well as localized RCC [11], [13], [21], [22], [23], [24], [25]. Several models involving CRP in predicting survival of patients with mRCC have been proposed [11], [25].

In addition to being an important prognostic factor, CRP could be an informative biomarker that reflects disease progression and efficacy of therapeutic intervention. Our previous report demonstrated that decrease of the posttreatment CRP level is associated with better prognosis for patients with muscle-invasive bladder cancer treated with chemoradiotherapy [20]. In patients with mRCC, immediate decrease of the CRP level after cytoreductive nephrectomy indicated better prognosis compared with patients without decrease of the CRP level [26].

We herein investigated further the CRP kinetics in patents with mRCC under multimodal therapy including cytokine therapy and metastasectomy as well as nephrectomy, and the prognostic impact of the CRP kinetics. Furthermore, the impact of normalized CRP period on overall survival period was also analyzed.

Section snippets

Patients

One hundred eight patients with mRCC were treated at our institute from 1994 to 2007. Patients were diagnosed, and the extent of disease was assessed on the basis of clinical finding, computed tomography scan, magnetic resonance imaging and/or bone scan. Thirty-seven of total 108 patients underwent prior nephrectomy and presented with metachronous metastasis. Of the remaining 71 patients without prior nephrectomy and with synchronous metastasis, 47 patients underwent nephrectomy. Finally, 24

Oncologic outcome

Clinicopathologic characteristics of the 108 patients were summarized in Table 1. Overall survival curves for the entire cohort of patients are shown in Fig. 2. During the follow-up period, a median of 18 mo (interquartile range [IQR]: 7–40 mo), 78 of the 108 patients (71%) died of disease and 3 of the 108 patients (3%) died of other causes. At the end of the follow-up, as of December 2007, 16 patients were alive with disease, with a median follow-up period of 24 mo (IQR, 15–57 mo), and 11

Discussion

In the present study, we demonstrated that CRP is a useful biomarker for patients with mRCC from two findings. First, CRP kinetics could predict prognosis of patients with mRCC. Second, the period with normalized CRP level was strongly correlated with survival period.

As reported previously [11], [13], [24], [25], patients without elevation of pretreatment CRP level have better prognosis compared with patients with elevated pretreatment CRP level. However, it has not been elucidated whether CRP

Conclusions

Our finding demonstrates that CRP kinetics have an impact on survival in patients with mRCC. Decrease of CRP level during treatment predicts better prognosis in patients with mRCC, and prolonged normalized CRP period is associated with prolonged survival. CRP can be a novel, widely available biomarker for patients with mRCC.

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