Prognostic Value of Hematologic Parameters in Patients with Metastatic Renal Cell Carcinoma Using Tyrosine Kinase Inhibitors

The incidence of kidney cancer has been increasing worldwide, accounting for approximately 2% of all cancers (Mathew et al., 2002). In 2010, 287,421 new cases and 122,302 deaths were estimated and, by 2015, 325,433 new cases and 138,629 deaths are expected to ocur (Ferlay et al., 2010). Five-year survival rates approximate 8% for patients with metastatic renal cell carcinoma (RCC). (AJCC Cancer Staging Manual, 2010) Chemotherapy is ineffective in treating kidney cancer; immunotherapy with high-dose interleukin-2 or interferon-alfa (INF-α) is effective in some patients (Yang et al., 2003). These agents are associated with low response rates (<15%) and significant toxicities, which often limit their use and affect patient quality of life (QoL) (Kapoor and Hotte, 2007). Vascular endothelial growth factor (VEGF) is primarly targeted in antiangiogenic treatment of solid tumors (Willett et al., 2004). Clinical trials showed antiangiogenic agents (such as sorafenib, sunitinib, bevasizumab and pazopanib) in advanced RCC have reported consistent prolongation of progression-free survival (PFS) and, in some cases, overall survival (OS) in both treatment-


Introduction
The incidence of kidney cancer has been increasing worldwide, accounting for approximately 2% of all cancers (Mathew et al., 2002). In 2010, 287,421 new cases and 122,302 deaths were estimated and, by 2015, 325,433 new cases and 138,629 deaths are expected to ocur (Ferlay et al., 2010). Five-year survival rates approximate 8% for patients with metastatic renal cell carcinoma (RCC). (AJCC Cancer Staging Manual, 2010) Chemotherapy is ineffective in treating kidney cancer; immunotherapy with high-dose interleukin-2 or interferon-alfa (INF-α) is effective in some patients (Yang et al., 2003). These agents are associated with low response rates (<15%) and significant toxicities, which often limit their use and affect patient quality of life (QoL) (Kapoor and Hotte, 2007).
Vascular endothelial growth factor (VEGF) is primarly targeted in antiangiogenic treatment of solid tumors (Willett et al., 2004). Clinical trials showed antiangiogenic agents (such as sorafenib, sunitinib, bevasizumab and pazopanib) in advanced RCC have reported consistent prolongation of progression-free survival (PFS) and, in some cases, overall survival (OS) in both treatment-

Prognostic Value of Hematologic Parameters in Patients with Metastatic Renal Cell Carcinoma Using Tyrosine Kinase Inhibitors
Seyda Gunduz 1 *, Hasan Mutlu 1 , Mukremin Uysal 2 , Hasan Senol Coskun 1 , Hakan Bozcuk 1 naive and previously treated patients (Cohen and Oudard, 2012). This targeted agents needs to new prognostic markers. Many factors, such as anatomic extent of disease, histopathology, clinical factors, affect the prognosis in patients with RCC (Heng et al., 2009). Prognositic value of peripheral blood markers has been present in many cancers (Ohno et al., 2010;Zheng et al., 2013).
The purpose of this study was to examine retrospectively the survival data of our patients with metastatic renal cell cancer who received tyrosine kinase inhibitors and to determine the prognostic value of different peripheral blood parameters in association with the treatment efficacy.

Patients
The medical files of the patients with metastatic renal cell cancer (RCC) were reviewed retrospectively. The study included 45 patients diagnosed with metastatic RCC previously treated with tyrosine kinases inhibitors from two center. These centers were Akdeniz University Hospital and Afyon Kocatepe University.

Treatment plan
All patients had received IFN-α therapy until progression or intolerance before tyrosine kinases inhibitors. Sunitinib, sorafenib and pazopanib were used in metastatic RCC treatment as tyrosine kinases inhibitors.
The disease progression status of patients was defined as increase in the dimensions of existing lesions or development of new metastases, as demonstrated by radiological imaging.

Statistical analysis
Overall survival (OS) was defined as the duration between the date of onset of a treatment and the date of death. Progression-free survival (PFS) was defined as the period of time between the initial administration of a treatment and the detection of the first tumor progression based on radiological criteria, or death. Survival was analyzed by the Kaplan-Meier survival analysis and the univariate Cox regression analysis. Variables with a value of p<0.10 in univariate analysis were also evaluated by multivariate analysis. A p value of less than 0.05 (p<0.05) was considered as statistically significant.

Patient, disease and treatment characteristics
In this study, we evaluated the data of 45 patients diagnosed with metastatic RCC. The study group consisted of all patients with metastatic RCC from two centers between of May 2009 and September 2013. The median follow-up period was 23.9 months. The median age of the patients was 63 years (ranging from 41 to 90 The patients with underwent nephrectomy were 31 (68.9%). In addition all patients had received subcutaneous IFN-α therapy prior to the treatment with oral tyrosine kinases inhibitors. In 77.8% of the patients were use sunitinib, 11.1% of them were use sorafenib and other patients were use pazopanib. Refer to Table 1 for the details.

Survival analysis
The median follow-up period was 23.9 months. During the treatment with tyrosine kinases inhibitors, the patients had a median PFS of 13.9 months [95% CI for HR (6.88-20.91)] and overall survival figure of 16.6 months [95% CI for HR (7.23-26.03)] (Figures 1 and 2).

Discussion
The results of our study showed that value of NLR was a prognostic for the patients with RCC who use tyrosine kinases inhibitors.
The systemic treatment of metastatic renal cell carcinoma (mRCC) has dramatically developed during recent years. Vascular endothelial growth factor (VEGF) pathway inhibitors are important agents in the treatment of RCC. Several studies have demonstrated the efficacy of VEGF-targeted agents in previously untreated patients with advanced or metastatic RCC and patients with RCC who have progressed after prior therapy (Motzer et al., 2007;Sternberg et al., 2010). Clinical efficacy has been reported for these agents associated with a median overall survival (OS) of 22.9-26.4 months, PFS of 8-9 months for sunitinib or sorafenib in first line treatment (Al-Marrawi et al., 2010;Motzer et al., 2011;Porta et al., 2011). Otherhand, patients with metastatic RCC and progression on first-line cytokine therapy median time to progression was 8.7 months with sunitinib (Motzer et al., 2006). In our study, the median progression-free survival was 13.9 months [95% CI for HR (6.88-20.91)] in patients treated with tyrosine kinases inhibitors , and overall survival was 16.9 months [95% CI for HR (7.23-26.03)] in secondline settings.
Neutrophilia maybe markers of inflammation related to the overproduction of cytokines as a result of increasing tumor burden or aggressive tumor biology. NLR is other marker of systemic inflammatory response. The prognostic role of tumor-infiltrating neutrophils, elevated blood neutrophils and elevated blood neutrophil/ lymphocyte ratio has been associated with poor clinical outcome in several human cancers, such as in renal cell carcinoma, melanoma, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, GIST, gastric, esophageal, lung, ovarian and head and neck cancer (Ohno et al., 2010;Donskov et al., 2013;Unal et al., 2013). Hanninen et al. (1996) reported the first report of neutrophils as an adverse prognostic factor for patients with metastatic renal cell carcinoma (mRCC). The recent studies have evaluated the association of pre-treatment neutrophil to lymphocyte ratio (NLR) with response rate, PFS and OS in patients treated with sunitinib for mRCC. This trials showed that a low baseline blood NLR ≤3 was independently correlated with response to sunitinib, and independently correlated with favorable PFS and OS (Hanninen et al., 1996;Dirican et al., 2013). We determined that PFS is significantly affected by NLR [p=0.031 calcium levels (p=0.018) with multivariate analysis. Median PFS was 23.9 vs 8.6 months in patients with NLR ≤2 vs NLR >2 (p=0.040). Our results indicate that NLR levels below 2 and calcium level below 9 mg/ dl increase PFS in patients with metastatic RCC who used tyrosine kinases inhibitors. Therefore, both of these should be considered to be positive predictive factors for survival. Morever in our study, we did not detect a significant relationship between the PFS and its predictive factors such as age, history of nephrectomy, white blood cell count before the treatment, neutrophil count, PLT count, eosinophil count and ALT levels.
In conclusion, anti VEGF targeted therapy is important for mRCC. This targeted agents needs to new prognostic markers. Metastatic RCC patients should have an assessment of degree of systemic inflammation at the prior the treatment. NLR is an easily measurable and cost effective parameter for show the systemic inflammation. This study shows that increased pretreatment NLR independent prognostic for in patients with metastatic RCC who use tyrosine kinases inhibitors.