C-reactive protein in patients with advanced metastatic renal cell carcinoma: Usefulness in identifying patients most likely to benefit from initial nephrectomy
© Ito et al.; licensee BioMed Central Ltd. 2012
Received: 3 April 2012
Accepted: 24 July 2012
Published: 2 August 2012
C-reactive protein (CRP) is considered a useful serum marker for patients with RCC. However, its clinical utility in advanced metastatic renal cell carcinoma (AM-RCC), particularly in deciding whether to perform nephrectomy at the onset, is not well studied.
Patients and methods
We retrospectively evaluated 181 patients with AM-RCC, including 18 patients underwent potentially curative surgery, 111 underwent cytoreductive nephrectomy, and 52 received medical treatment only. CRP cutoff points were determined by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier and Cox regression analyses were used for survival tests.
ROC analysis suggested that grouping patients according to 3 CRP ranges was a rational model. Patients with highly elevated CRP (≥67.0 mg/L) presented remarkably poor prognosis despite treatment (nephrectomy or medical treatment only). Cox regression models demonstrated that risk factors of overall survival for patients who underwent nephrectomy were the CRP ranges defined in this study (≤18.0 mg/L, >18.0 and <67.0 mg/L, and ≥67.0 mg/L), ECOG PS (0, 1, and ≥2), and number of metastatic organ sites (0–1 and ≥2). The retrospective design is a limitation of this study.
Our study demonstrated that the serum CRP level is a statistically significant prognostic parameter for patients with AM-RCC. The data also indicated that pretreatment serum CRP level provides useful prognostic information that helps in deciding whether to perform initial nephrectomy for patients with AM-RCC.
KeywordsC-reactive protein Rena cell carcinoma Prognosis
Advanced metastatic-renal cell carcinoma (AM-RCC) is associated with a poor prognosis, with the 5-year survival rate being less than 20% for patients presenting with stage IV disease [1, 2]. RCC is known to be resistant to conventional chemotherapy and radiation. Cytokine-based immunotherapies, including interferon-alpha (IFN-α) and interleukin-2 (IL-2), elicited limited response in a small subset of AM-RCC cases [3, 4]. Over the last few years, novel molecular targeting agents, such as antiangiogenic drugs and mammalian target of rapamycin (mTOR) inhibitors, have been developed, and they have assumed a predominant role in the several treatment options currently available for AM-RCC. On the other hand, surgical interventions, including cytoreductive nephrectomy and/or metastasectomy, have also proven to be beneficial to some extent for patients with AM-RCC, in terms of both survival and quality of life [3–5]. Surgical removal of the majority of tumor burden can be expected to diminish the source of tumor-promoting growth factors or immunosuppressive cytokines, although this has not yet been confirmed [3, 4]. Currently, an important concern is that no consensus has been established on the criteria for identifying patients with AM-RCC who are most likely to benefit from nephrectomy and/or metastasectomy performed at the onset [4–7].
C-reactive protein (CRP) is an acute-phase reactant protein exclusively synthesized by hepatocytes. The serum concentration of CRP rises as much as 1000-fold in immediate response to cytokines or chemical mediators released in various pathological conditions, including acute inflammation, infection, tissue or cell necrosis, and some malignancies [7, 8]. Several studies have reported that CRP is a useful serum marker for patients with RCC, and elevated serum CRP levels have been shown to be associated with tumor aggressiveness, recurrence, and poor prognosis [8–11]. However, its clinical utility in AM-RCC, particularly in deciding whether to perform surgical interventions at the onset, has not been studied well. We retrospectively investigated the role of CRP as a prognostic marker for patients with AM-RCC. We also explored its usefulness in identifying patients who are most likely to benefit from early nephrectomy.
Patients and treatment
Clinicopathologic characteristics of patients with advanced metastatic RCC treated with any kind of nephrectomy and no nephrectomy
Number of patients (%)
No. of metastatic organ sites
Others or not determined
Tumor grading (Fuhrman)
Clinical and laboratory assessment
All patients were staged according to the 2002 TNM classification system . We collected data on the following clinicopathologic factors from the medical records of the patients: patient age; sex; Eastern Cooperative Oncology Group performance status (ECOG PS); maximum tumor diameter; number of metastatic organ sites; and levels of hemoglobin (Hb), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), corrected calcium, and CRP when a patient was first seen. The Hb level was categorized using a cutoff value of the lower normal limit, and LDH and ALP levels, using a cutoff value of 1.5× the normal limit; corrected calcium was considered normal up to 10 mg/dL, as reported previously [1, 12, 13]. Maximum tumor diameter was divided into two groups using median value.
The overall survival (OS) period was calculated from the date of nephrectomy to death or last follow-up. For patients who did not undergo nephrectomy, the survival period was measured from the first diagnosis of RCC to death or last follow-up. The differences between groups were examined using the Mann–Whitney U or chi-square test depending on the data set.
We determined the cutoff point of CRP according to the sensitivity and specificity levels derived from the receiver operating characteristic (ROC) curve plotted using death before median survival period in the patient cohort that underwent nephrectomy. Survival probabilities were estimated using the Kaplan-Meier method, and the resultant curves were statistically tested by the log-rank method. Cox proportional hazards model was used for univariate and multivariate analyses. Significance was set at P < 0.10, which was used as the criterion for determining variable entry and removal from the multivariate analysis. All data were analyzed using the SPSS software package (SPSS, Chicago, Illinois). All statistical tests were two-sided and were considered to be statistically significant for P < 0.05.
We initially tried to figure out what kind of clinical factors might influence on the selection of initial nephrectomy for AM-RCC patient although the study was retrospective, non-randomized observational setting. We therefore compared the clinicopathologic characteristics of patients who underwent curative or cytoreductive nephrectomy with those of patients who did not undergo nephrectomy. As expected, older patient age (P = 0.003), larger tumor size (P = 0.004), and poorer ECOG PS (P < 0.001) were observed in the non-nephrectomy group compared to the nephrectomy group (Table 1). With respect to the metastatic organ sites, only the liver showed a higher incidence in the non-nephrectomy group than in the other group (P = 0.008); no apparent intergroup differences were noted in the incidence of metastasis at any other organ sites (P = 0.295; Table 1).
C-reactive protein and patient survival
Since patients with highly elevated (≥67.0 mg/L) levels of CRP showed poor prognosis despite the treatment procedures, i.e., nephrectomy or medical treatment only (median OS: 4.20 and 1.54 months, respectively), we compared these 2 groups. Kaplan-Meier analysis showed that the 2 groups did not differ statistically (log-rank: P = 0.703). Although the 2 groups differed slightly with respect to patient characteristics and backgrounds, the data suggested that initial nephrectomy did not seem to provide substantial survival advantages for patients with highly elevated CRP levels.
CRP as an independent prognostic parameter for AM-RCC
Univariate and multivariate Cox regression analysis of overall survival among patients AM-RCC who underwent nephrectomy of any kind (n = 81)
≥Lower normal limit
<Lower normal limit
≦Normal limit × 1.5
>Normal limit × 1.5
≦Normal limit × 1.5
>Normal limit × 1.5
Corrected Ca, mg/dL
Max. tumor diameter, cm
No. of metastatic organ sites
0 ≥ 67.0
CRP is a standardized and widely used serum indicator of acute-phase response in conditions such as acute inflammations, infections, tissue or organ necrosis, and malignancies . Some types of RCCs can induce systemic inflammations by expressing various cytokines such as IL-1, tumor necrosis factor, and mostly IL-6 . In vitro experimental studies showed some renal tumors themselves are actually capable of producing IL-6 . Furthermore, RCC, especially of the aggressive phenotype, is often accompanied by tumor necrosis . Therefore, tumor status and aggressiveness can be directly reflected by the serum CRP levels of patients with AM-RCC. Additionally, in case of other malignancies, CRP had been found to inhibit apoptosis of carcinoma cells, thereby directly regulating tumor cell growth and survival . In fact, we often encounter cases of AM-RCC in which the patient’s CRP level fluctuates in accordance with disease control and/or progression. Several studies have also indicated that elevated CRP is a poor prognostic indicator for RCC [9–11, 18, 19]. However, almost all the CRP cutoff points reported previously have been single values. These cutoff points range from 1.0 to 10.0 mg/L and vary widely from study to study, despite the fact that in the majority of studies, the cutoff point was defined on the basis of the normal values [9–11, 18, 19]. In the current study, we found that over 70% of the patients with AM-RCC showed abnormal CRP values, with a relatively wide dynamic range of up to 200 mg/L (Figure 2). In fact, when we initially applied previously reported cutoff points to our patient cohort, we were unable to define any CRP-based grouping system that could afford a rational assessment of survival risk (data not shown). In this study, we initially determined the 2 CRP cutoff points 18.0 and 67.0 mg/L in the nephrectomy patient cohort by means of ROC analysis. We then found that the CRP 3 grouping was a more suitable model for the risk stratification of AM-RCC patients because it was also applicable for patients who did not undergo nephrectomy (Figure 5).
A number of prognostic parameters have been studied for patients with localized, metastatic, or all-stage RCC [1, 2, 16, 19–27]. Among the parameters defined for AM-RCC, the most well-established and validated ones are Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors  and predictors of short survival proposed by the NCCN practice guidelines . In these models, however, CRP has not been enlisted as a significant factor. In our Cox models, we found that the risk factors associated with shorter survivals were high CRP level, low ECOG PS, and high number of metastatic organ sites (Table 2). On the other hand, Hb and ALP levels were not found to be independent parameters. Moreover, sex, maximum tumor diameter, LDH and corrected calcium levels did not appear to be statistically significant factors even in the univariate analyses. Thus, our results were considerably different from the recommendations of the MSKCC and NCCN guidelines [1, 12]. One of the major reasons for this discrepancy should be the treatment modalities. In our regression model, all patients underwent nephrectomy as the initial treatment. On the other hand, the prognostic factors defined in the MSKCC or NCCN guidelines were originally elucidated from patients receiving non-surgical medical treatments. Another possible reason might be the racial differences. Enrolled patients in our study were Japanese Asian populations. Naito S, et al. suggested that Japanese patients with AM-RCC showed better prognosis than non-Asian cohort . Such racial differences might affect the biological character of tumors, leading to differences in present report. On the basis of our data, we recommend that for patients with AM-RCC who are being considered for nephrectomy as the initial treatment option, more importance should be given to the CRP levels, ECOG PS, and the number of metastatic organ sites than other patient characteristics, such as ALP, Hb, LDH, and serum Ca levels.
Reports indicate that surgical complications occur in 20–22 % of patients with AM-RCC, and therefore, surgical approaches should not be adopted indiscriminately [5, 6]. Our data revealed that the patient group with highly elevated CRP (≥67.0 mg/L) showed very poor prognosis despite of treatment (median OS: 4.20 months in the nephrectomy group and 1.54 months in the non-nephrectomy group) (Figures 4 and 5). In this patient subgroup, the indications of initial surgical intervention should be assessed very carefully. On the other hand, the normal/mildly elevated CRP (≤18.0 mg/L) group showed relatively good prognosis even for patients who did not undergo nephrectomy (median OS: 24.2 months; Figure 5). Our data also suggested that the initial nephrectomy seemed to provide considerable survival advantages to patients with normal/mildly elevated and presumably elevated CRP levels (Figure 4). Thus, surgical approaches appear to be beneficial for these patient groups although other parameters need to be evaluated to validate this finding.
The majority of the patients analyzed in this study belonged to the so-called cytokine era. Currently, a number of treatment options, such as surgery, immunotherapy, and a series of molecular targeting agents, are available for patients with AM-RCC. It has been well-demonstrated that both MSKCC risk factors and NCCN guideline parameters, which were originally established in the cytokine era, are useful even in the molecular targeting era. Therefore, we expect that the current CRP grouping model will be important in the risk classification of patients with AM-RCC, even in the current molecular targeting era. Further prospective studies are now required to validate our findings.
There are inherent limitations to this study. Because of its retrospective design, the confounding factors and measurement bias cannot be reduced as much as they could in prospective, randomized studies. Especially, there is clearly a selection bias in any comparison between the nephrectomy and non-nephrectomy groups since the latter were clearly more advanced/unresectable/non-surgical candidates. However, despite of no clear criteria whether surgery was performed or not, Table 1 revealed significant differeneces; patient age, tumor size, ECOG PS and liver metastasis. That suggested that these parameters had impacts on our decision making. We believed that might be also useful information for clinical practice [3, 4, 6].
Our study demonstrated that the serum CRP level is a statistically significant prognostic parameter for patients with AM-RCC. Risk factors of OS were CRP (≤18.0 mg/L, >18.0 and <67.0 mg/L, and ≥67.0 mg/L), ECOG PS (0, 1, and ≥2), number of metastatic organ sites (0–1 and ≥2). The study also revealed that patients with highly elevated CRP levels (≥67.0 mg/L) had a considerably poor prognosis despite treatment. The data indicated that pretreatment serum CRP level could be one of the most reliable prognostic factors that can help decide whether to perform surgical procedures for patients with AM-RCC.
Advanced Metastatic Renal Cell Carcinoma
- ECOG PS:
Eastern Cooperative Oncology Group Performance Status
Receiver Operating Characteristic.
- Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999, 17: 2530-2540.PubMedGoogle Scholar
- Mekhail TM, Abou-Jawde RM, Boumerhi G, et al: Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005, 23: 832-841. 10.1200/JCO.2005.05.179.View ArticlePubMedGoogle Scholar
- Russo P: Multi-modal treatment for metastatic renal cancer: the role of surgery. World J Urol. 2010, 28: 295-301. 10.1007/s00345-010-0530-x.View ArticlePubMedGoogle Scholar
- Brian I R, Steven C C, Bernard E: Renal cell carcinoma. Lancet. 2009, 373: 1119-1132. 10.1016/S0140-6736(09)60229-4.View ArticleGoogle Scholar
- Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001, 345: 1655-1659. 10.1056/NEJMoa003013.View ArticlePubMedGoogle Scholar
- Russo P, O'Brien MF: Surgical intervention in patients with metastatic renal cancer: metastasectomy and cytoreductive nephrectomy. Urol Clin North Am. 2008, 35: 679-686. 10.1016/j.ucl.2008.07.009.View ArticlePubMedGoogle Scholar
- Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED: Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004, 171: 1071-1076. 10.1097/01.ju.0000110610.61545.ae.View ArticlePubMedGoogle Scholar
- Allin KH, Nordestgaard BG: Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci. 2011, 48: 155-170. 10.3109/10408363.2011.599831.View ArticlePubMedGoogle Scholar
- Saito K, Kihara K: C-reactive protein as a biomarker for urological cancers. Nat Rev Urol. 2011, 8: 659-666.PubMedGoogle Scholar
- Saito K, Tatokoro M, Fujii Y, et al: Impact of C-reactive protein kinetics on survival of patients with metastatic renal cell carcinoma. Eur Urol. 2009, 55: 1145-1153. 10.1016/j.eururo.2008.10.012.View ArticlePubMedGoogle Scholar
- Johnson TV, Abbasi A, Owen-Smith A, et al: Absolute preoperative C-reactive protein predicts metastasis and mortality in the first year following potentially curative nephrectomy for clear cell renal cell carcinoma. J Urol. 2010, 183: 480-485. 10.1016/j.juro.2009.10.014.View ArticlePubMedGoogle Scholar
- Mickisch G, Carballido J, Hellsten S, Schulze H, Mensink H: European Association of Urology.: Guidelines on renal cell cancer. Eur Urol. 2001, 40: 252-255. 10.1159/000049783.View ArticlePubMedGoogle Scholar
- Hudes G, Carducci M, Tomczak P, et al: Global ARCC Trial.: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007, 356: 2271-2281. 10.1056/NEJMoa066838.View ArticlePubMedGoogle Scholar
- Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999, 340: 448-454. 10.1056/NEJM199902113400607.View ArticlePubMedGoogle Scholar
- Koo AS, Armstrong C, Bochner B, et al: Interleukin-6 and renal cell cancer: production, regulation, and growth effects. Cancer Immunol Immunother. 1992, 35: 97-105. 10.1007/BF01741856.View ArticlePubMedGoogle Scholar
- Zigeuner R, Hutterer G, Chromecki T, et al: External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology. Eur Urol. 2010, 57: 102-109. 10.1016/j.eururo.2008.11.033.View ArticlePubMedGoogle Scholar
- Yang J, Wezeman M, Zhang X, et al: Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell. 2007, 12: 252-265. 10.1016/j.ccr.2007.08.008.View ArticlePubMedGoogle Scholar
- Ramsey S: The role of the systemic inflammatory response as a biomarker in immunotherapy for renal cell cancer. Mol Diagn Ther. 2009, 13: 277-281. 10.1007/BF03256333.View ArticlePubMedGoogle Scholar
- Casamassima A, Picciariello M, Quaranta M, 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. 2005, 173: 52-55. 10.1097/01.ju.0000146713.50673.e5.View ArticlePubMedGoogle Scholar
- Eggener SE, Yossepowitch O, Pettus JA, Snyder ME, Motzer RJ, Russo P: Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. J Clin Oncol. 2006, 24: 3101-3106. 10.1200/JCO.2005.04.8280.View ArticlePubMedGoogle Scholar
- Sorbellini M, Kattan MW, Snyder ME, et al: A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol. 2005, 173: 48-51. 10.1097/01.ju.0000148261.19532.2c.View ArticlePubMedGoogle Scholar
- Naito S, Yamamoto N, Takayama T, et al: Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients. Eur Urol. 2010, 57: 317-325. 10.1016/j.eururo.2008.12.026.View ArticlePubMedGoogle Scholar
- Escudier B, Choueiri TK, Oudard S, et al: Prognostic factors of metastatic renal cell carcinoma after failure of immunotherapy: new paradigm from a large phase III trial with shark cartilage extract AE 941. J Urol. 2007, 178: 1901-1905. 10.1016/j.juro.2007.07.035.View ArticlePubMedGoogle Scholar
- Motzer RJ, Bacik J, Schwartz LH, et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004, 22: 454-463.View ArticlePubMedGoogle Scholar
- Motzer RJ, Bacik J, Mazumdar M: Prognostic factors for survival of patients with stage IV renal cell carcinoma: Memorial Sloan-Kettering Cancer Center experience. Clin Cancer Res. 2004, 10: 6302S-6303S. 10.1158/1078-0432.CCR-040031.View ArticlePubMedGoogle Scholar
- Karakiewicz PI, Suardi N, Capitanio U, et al: Conditional survival predictions after nephrectomy for renal cell carcinoma. J Urol. 2009, 182: 2607-2612. 10.1016/j.juro.2009.08.084.View ArticlePubMedGoogle Scholar
- Galfano A, Novara G, Iafrate M, et al: Mathematical models for prognostic prediction in patients with renal cell carcinoma. Urol Int. 2008, 80: 113-123. 10.1159/000112599.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/337/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.