**3. Biomarkers of response to sunitinib in renal tumors**

### **3.1. Prognostic model**

In the cytokine era, Motzer et al. [13] reported Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, which is based on data from 463 patients with advanced renal tumor who were treated with IFN-α cytokine therapy as first-line systemic therapy. The MSKCC risk classification extracted five variable risk factors for short survival: low Karnof‐ sky performance status (PS) (< 80%), high lactate dehydrogenase (> 1.5 times the upper limit of normal), low serum hemoglobin, high corrected serum calcium (> 10 mg/dL), and time from initial renal tumor diagnosis to IFN-α therapy of less than one year. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two risk factors (intermediate risk), and those with three or more risk factors (poor risk). The median time to death was 30, 14, and 5 months in the favorable, intermediate, and poor-risk groups, respectively [13]. These five risk criteria are now most frequently used prognostic model for patients with advanced renal tumor.

In the era of targeted therapy, Heng et al. [14] reported a new prognostic model that added platelet and neutrophil counts to the MSKCC model from a large multicenter study of 645 patients with metastatic renal tumor who were treated with targeted therapy. This study in‐ cluded three groups of patients: 396 patients treated with sunitinib, 200 patients treated with sorafenib, and 49 patients treated with bevacizumab. Four of the five adverse prognostic fac‐ tors according to the MSKCC risk classification−low hemoglobin, high corrected serum cal‐ cium, low Karnofsky PS, and time from the initial renal tumor diagnosis to the start of treatment of less than one year−emerged as independent predictors of poor survival. Addi‐ tionally, platelets greater than the upper limit of normal range, and neutrophils greater than the upper limit of normal range, emerged as independent adverse prognostic factors. MSKCC model with the addition of platelet and neutrophil counts can be incorporated into patient care of targeted therapies [14].

### **3.2. C-reactive protein**

C-reactive protein (CRP), a non-specific inflammatory acute-phase protein, is a representa‐ tive marker of systemic inflammatory response. CRP levels correlate with the production of proinflammatory cytokines, such as interleukin (IL) -6 [15], and with tumor progression [16, 17]. It has been recognized as an important prognostic marker in the cytokine era. Atzpo‐ dien et al. [16] reported data from 425 patients who received cytokine-based home therapy. On multivariate analysis, elevated CRP (≥ 1.1 mg/dL) was a poor prognostic factor, and Kaplan-Meier analysis demonstrated that patients with elevated CRP had significantly worse over‐ all survival [16]. Casamassima et al. [17] reported that normal CRP (≤ 0.8 mg/dL) was the most independent prognostic factor for 110 patients treated with IL-2-based immunotherapy. Ram‐ sey et al. [18] investigated the Glasgow Prognostic Score, which is based on a combination of hypoalbuminemia and elevated CRP (> 1.0 mg/dL). They found that CRP was independent‐ ly associated with cancer-specific survival in 119 patients receiving immunotherapy [18]. Saito et al. [19] described that CRP kinetics have an impact on survival in patients with metastatic renal tumor treated with immunotherapy and/or metastasectomy. A decrease of CRP level during treatment predicts better prognosis in patients with metastatic renal tumor, and pro‐ longed normalized CRP period is associated with prolonged survival [19].

41 consecutive patients between December 2008 and August 2011 were enrolled in this study. All patients had histologically proven clear-cell renal tumor. Non-tumor variables which were selected from pretreatment characteristics and treatment-related adverse events were ana‐ lyzed on univariate and multivariate logistic regression analysis. Pretreatment characteris‐ tics were age, gender, Eastern Cooperative Oncology Group (ECOG) PS 0, MSKCC nonpoor (favorable and intermediate) risk, first-line treatment, and normal CRP. Treatmentrelated adverse events were hypertension, hand-foot skin reaction (HFS), stomatitis, diarrhea, altered taste, fatigue, leukopenia, anemia, thrombocytopenia, increased creatinine, and thyroidstimulating hormone (TSH) abnormalities. On univariate analyses among pretreatment char‐ acteristics, MSKCC non-poor risk classification and normal CRP level were significantly correlated with response to treatment (*P* = 0.0206 and 0.0011, respectively). Among adverse events, HFS, altered taste, fatigue, and leukopenia were significantly corralated with re‐ sponse to treatment (*P* = 0.0069, 0.0064, 0.0238, and 0.0337, respectively). Variable values in the multivariate analysis included MSKCC non-poor risk classification, normal CRP, HFS, al‐ tered taste, fatigue, and leukopenia. After adjusting for differences in these variables, nor‐

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35

mal CRP was independently associated with response to treatment (*P* = 0.0163).

observed in the normal CRP cohort was statistically significant (*P* = 0.0022).

Male 10 (76.9) 20 (71.4) Female 3 (23.1) 8 (28.6)

Median 63 64 Range 46−77 36−80 Mean ± standard deviation 64.8 ± 9.0 63.2 ± 9.1

**Normal CRP (≤ 0.30 mg/dL)**

Gender (*n* (%)) 0.7118

Age (years) 0.5953

13 (31.7%) 28 (68.3%)

**Elevated CRP (> 0.30 mg/dL)**

*P***-value**

Patients were grouped into two cohorts: those with normal CRP levels (≤ 0.30 mg/dL) and those with elevated CRP levels (> 0.30 mg/dL), according to the normal values provided by the manufacturer. The cohort with normal CRP comprised 10 males and 3 females (total 13 patients; 31.7%) with a median age of 63 years (range 46−77 years). The elevated CRP cohort comprised 20 males and 8 females (total 28 patients; 68.3%) with a median age of 64 years (range 36−80 years). MSKCC risk classification was favorable for 15.4% of the normal CRP cohort and intermediate for 86.4%. In contrast, in the elevated CRP cohort, MSKCC risk clas‐ sification was favorable for 21.4%, intermediate for 46.4%, and poor for 32.2%. The differ‐ ence in risk classification between the two groups was statistically significant (*P* = 0.0377). There were no statistically significant differences in any other pretreatment variables and tu‐ mor characteristics. The rate of partial response plus stable disease to treatment was 84.6% for the normal CRP cohort and 35.7% for the elevated CRP cohort. The higher response rate


**Table 1.** Univariate and multivariate logistic regression analyses for selected variables

In the targeted therapy era, Fujita et al. [20] recently reported that CRP is an independent prognostic indicator for patients with advanced renal tumor treated with sunitinib. A total of 41 consecutive patients between December 2008 and August 2011 were enrolled in this study. All patients had histologically proven clear-cell renal tumor. Non-tumor variables which were selected from pretreatment characteristics and treatment-related adverse events were ana‐ lyzed on univariate and multivariate logistic regression analysis. Pretreatment characteris‐ tics were age, gender, Eastern Cooperative Oncology Group (ECOG) PS 0, MSKCC nonpoor (favorable and intermediate) risk, first-line treatment, and normal CRP. Treatmentrelated adverse events were hypertension, hand-foot skin reaction (HFS), stomatitis, diarrhea, altered taste, fatigue, leukopenia, anemia, thrombocytopenia, increased creatinine, and thyroidstimulating hormone (TSH) abnormalities. On univariate analyses among pretreatment char‐ acteristics, MSKCC non-poor risk classification and normal CRP level were significantly correlated with response to treatment (*P* = 0.0206 and 0.0011, respectively). Among adverse events, HFS, altered taste, fatigue, and leukopenia were significantly corralated with re‐ sponse to treatment (*P* = 0.0069, 0.0064, 0.0238, and 0.0337, respectively). Variable values in the multivariate analysis included MSKCC non-poor risk classification, normal CRP, HFS, al‐ tered taste, fatigue, and leukopenia. After adjusting for differences in these variables, nor‐ mal CRP was independently associated with response to treatment (*P* = 0.0163).

dien et al. [16] reported data from 425 patients who received cytokine-based home therapy. On multivariate analysis, elevated CRP (≥ 1.1 mg/dL) was a poor prognostic factor, and Kaplan-Meier analysis demonstrated that patients with elevated CRP had significantly worse over‐ all survival [16]. Casamassima et al. [17] reported that normal CRP (≤ 0.8 mg/dL) was the most independent prognostic factor for 110 patients treated with IL-2-based immunotherapy. Ram‐ sey et al. [18] investigated the Glasgow Prognostic Score, which is based on a combination of hypoalbuminemia and elevated CRP (> 1.0 mg/dL). They found that CRP was independent‐ ly associated with cancer-specific survival in 119 patients receiving immunotherapy [18]. Saito et al. [19] described that CRP kinetics have an impact on survival in patients with metastatic renal tumor treated with immunotherapy and/or metastasectomy. A decrease of CRP level during treatment predicts better prognosis in patients with metastatic renal tumor, and pro‐

*P*-value

MSKCC non-poor 0.150 (0.026−0.864) 0.0206 0.632 (0.058−6.850) 0.7042

Normal CRP 17.600 (1.961−157.970) 0.0011 13.525 (1.111−164.602) 0.0163

HFS 6.500 (1.537−27.490) 0.0069 2.272 (0.324−15.930) 0.4104

Altered taste 8.250 (1.498−45.436) 0.0064 4.422 (0.533−36.655) 0.1517 Fatigue 5.133 (1.131−23.303) 0.0238 1.572 (0.192−12.841) 0.6740 Leukopenia 8.333 (0.867−80.130) 0.0337 5.436 (0.190−155.246) 0.2717

In the targeted therapy era, Fujita et al. [20] recently reported that CRP is an independent prognostic indicator for patients with advanced renal tumor treated with sunitinib. A total of

Odds Ratio

(95% Confidence Interval)

*P*-value

longed normalized CRP period is associated with prolonged survival [19].

Variable Univariate Multivariate

(95% Confidence Interval)

Odds Ratio

Age 0.988 (0.920−1.061) 0.7410 Gender 0.573 (0.139−2.355) 0.4384 ECOG PS0 4.200 (0.884−19.947) 0.0598

First-line 0.879 (0.238−3.249) 0.8468

Hypertension 3.667 (0.954−14.094) 0.0523

Stomatitis 3.200 (0.826−12.404) 0.0844 Diarrhea 1.375 (0.368−5.136) 0.6347

Anemia 1.771 (0.392−8.003) 0.4559 Thrombocytopenia 758.701 (0.000) 0.0670 Increased creatinine 2.182 (0.566−8.415) 0.2505 TSH abnormalities 2.812 (0.734−10.774) 0.1255

**Table 1.** Univariate and multivariate logistic regression analyses for selected variables

Pretreatment

34 Renal Tumor

Adverse events

Patients were grouped into two cohorts: those with normal CRP levels (≤ 0.30 mg/dL) and those with elevated CRP levels (> 0.30 mg/dL), according to the normal values provided by the manufacturer. The cohort with normal CRP comprised 10 males and 3 females (total 13 patients; 31.7%) with a median age of 63 years (range 46−77 years). The elevated CRP cohort comprised 20 males and 8 females (total 28 patients; 68.3%) with a median age of 64 years (range 36−80 years). MSKCC risk classification was favorable for 15.4% of the normal CRP cohort and intermediate for 86.4%. In contrast, in the elevated CRP cohort, MSKCC risk clas‐ sification was favorable for 21.4%, intermediate for 46.4%, and poor for 32.2%. The differ‐ ence in risk classification between the two groups was statistically significant (*P* = 0.0377). There were no statistically significant differences in any other pretreatment variables and tu‐ mor characteristics. The rate of partial response plus stable disease to treatment was 84.6% for the normal CRP cohort and 35.7% for the elevated CRP cohort. The higher response rate observed in the normal CRP cohort was statistically significant (*P* = 0.0022).



**Normal CRP (≤ 0.30 mg/dL)**

No. metastatic sites (*n* (%)) 0.1929

Treatment (*n* (%)) 0.2122

Responses (*n* (%)) 0.0022

The median progression-free survival time for the elevated CRP cohort was 6.0 months. In contrast, the median progression-free survival time for the normal CRP cohort was signifi‐

Prostate 1 −

1 6 (46.1) 8 (28.6) ≥ 2 6 (46.1) 20 (71.4)

First-line 3 (23.1) 13 (46.4) Second-line 6 (46.1) 6 (21.4) Third-line 4 (30.8) 9 (32.2)

Partial response plus stable disease 11 (84.6) 10 (35.7)

**Figure 1.** Kaplan-Meier progression-free survival for patients grouped by CRP level

**Table 2.** Patient characteristics grouped by CRP level

cantly longer, at 19.0 months (log-rank *P* = 0.0361).

**Elevated CRP (> 0.30 mg/dL)**

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*P***-value**

37


**Table 2.** Patient characteristics grouped by CRP level

**Normal CRP (≤ 0.30 mg/dL)**

ECOG PS (*n* (%)) 0.0595

MSKCC risk classification (*n* (%)) 0.0377

Prior nephrectomy (*n* (%)) 0.2767

T stage (*n* (%)) 0.8187

Grade (*n* (%)) 0.6628

Prior immunotherapy (*n*) 0.2482

Prior targeted therapy (*n*) 0.8651

0 12 (92.3) 18 (64.3) ≥ 1 1 (7.7) 10 (35.7)

Favorable 2 (15.4) 6 (21.4) Intermediate 11 (84.6) 13 (46.4) Poor 0 (0) 9 (32.2)

Yes 12 (92.3) 22 (78.6) No 1 (7.7) 6 (21.4)

T1 or T2 6 (46.2) 14 (50.0) ≥ T3 7 (53.8) 14 (50.0)

1 or 2 9 (69.2) 17 (60.7) 3 3 (23.1) 8 (28.6)

IFN-α 9 14 IL-2 and IFN-α 3 6

Sorafenib 5 10

Lung 12 21 Bone 2 12 Lymph nodes 3 7 Brain 1 3 Pancreas − 4 Adrenal − 4 Skin − 3 Kidney − 2 Local − 2 Liver − 2

Metastatic sites (*n*)

36 Renal Tumor

**Elevated CRP (> 0.30 mg/dL)**

*P***-value**

The median progression-free survival time for the elevated CRP cohort was 6.0 months. In contrast, the median progression-free survival time for the normal CRP cohort was signifi‐ cantly longer, at 19.0 months (log-rank *P* = 0.0361).

**Figure 1.** Kaplan-Meier progression-free survival for patients grouped by CRP level

CRP is a significant independent prognostic indicator for patients with advanced renal tu‐ mor treated with sunitinib. Pretreatment CRP level could be a useful biomarker for response to sunitinib treatment [20].

using logistic regression model (*P* = 0.009). Furthermore, grade 3 hypertension was correlat‐ ed with a better outcome (*P* = 0.03). The appearance of hypertension, particularly grade 3, was associated with higher treatment response to sunitinib in metastatic renal tumors. Early and intensive antihypertensive therapy with the goal of maintaining the sunitinib use may

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39

Overall, hypertension related to sunitinib was a positive predictive factor associated with significantly better objective response rate, longer progression-free survival and overall sur‐

Treatment-related hypothyroidism has been reported a useful predictor of progression-free survival for metastatic renal tumors undergoing treatment with sunitinib [28]. In the 52 patients with metastatic renal tumor treated with sunitinib, 13 patients (25.0%) developed hypothyr‐ oidism during treatment. Subclinical hypothyroidism was defined as serum TSH above the upper limit of normal, with total triiodothyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Hypothyroidism was associated with a longer progression-free survival time (*P* = 0.032).

Han et al. [29] reported the initial tumor enhancement on contrast-enhanced computed to‐ mography (CT) could be useful as a clinical predictor during targeted therapy in 198 meta‐ static lesions of 46 patients. On multivariate analyses, tumor enhancement and enhancement pattern were associated with objective responses (*P* = 0.003 and 0.028, respectively). Addi‐ tionally, tumor enhancement was associated with tumor size reduction (*P* = 0.004). On Cox proportional hazards models, only tumor enhancement was associated significantly with the time to size reduction and progression-free survival time (*P* = 0.03 and 0.015, respective‐ ly). Tumor enhancement on contrast-enhanced CT was associated with tumor size reduc‐ tion, time to response, and time to progression of individual metastases in patients with

Kayani et al [30] revealed prognostic significance of 18F-fluorodeoxyglucose-positron emis‐ sion tomography (FDG-PET)/CT as a biomarker of response to sunitinib. A total of 44 pa‐ tients with newly diagnosed untreated metastatic renal tumor were enrolled in this study. 18F-FDG-PET/CT scans were conducted before, after 4 weeks, and after 16 weeks of sunitinib given. On multivariate analysis, a high SUVmax and an increased number of PET-positive le‐ sions correlated with shorter overall survival. The early metabolic responses are associated with a pharmacodynamic effect of drug and it is not until later identification with acquired

Yuasa et al. [31] reported that initial tumor size is inversely associated with the tumor reduc‐ tion rate of individual metastatic sites and primary tumors in patients with metastatic renal tumor who underwent targeted therapy. A data from 139 metastatic and 16 primary lesions

Hormone replacement with 1-thyroxine did not have an influence on survival [28].

improve response rate in those patients [27].

*3.3.2. Hypothyroidism*

**3.4. Others**

resistance occurs [30].

vival in patients with metastatic renal tumor treated with sunitinib.

metastatic renal tumor who received targeted therapy [29].

### **3.3. Selected adverse events**

Sunitinib has been related a variety of adverse events, key notable clinical adverse events included diarrhea (61%), fatigue (54%), hypertension (30%), stomatitis (30%), HFS (29%), and asthenia (20%) [4]. Laboratory abnormalities also found that included leukopenia (78%), anemia (79%), increased creatinine (70%), and thrombocytopenia (68%) [4]. If adverse events depends on the degree of systemic exposure to sunitinib, on which clinical efficacy also de‐ pends, adverse events might be potential predictors of sunitinib efficacy [21]. Several au‐ thors have described the correlation between sunitinib responses and selected treatmentrelated adverse events.

### *3.3.1. Hypertension*

Hypertension is commonly associated with targeted therapy. It develops when VEGF stimu‐ lates production of nitric oxide and prostacyclins in vascular endothelial cells [22, 23], vaso‐ dilatory mechanisms become inhibited, and peripheral vascular resistance increases, leading to increased blood pressure.

Rini et al. [24] demonstrated that sunitinib-associated hypertension is associated with im‐ proved clinical outcomes without clinically significant increases in hypertension-associated adverse events. This analysis included large pooled data from four clinical trilas of 4915 pa‐ tients with metastatic renal tumor who were treated with sunitinib. Sunitinib-induced hy‐ pertension had significantly better outcomes than those without treatment-induced hypertension in the objective response rate (54.8% *vs* 8.7%), the median progression-free sur‐ vival time (12.5 *vs* 2.5 months), and the median overall survival time (30.9 *vs* 7.2 months, *P*< 0.001 for all) [24].

Bono et al. [25] reported that sunitinib-induced hypertension was associated with frequent tumor response (*P* = 0.001), significantly longer disease progression time (*P* = 0.0003), and overall survival time (*P* = 0.001). On multivariate analysis including the variables of pretreat‐ ment hemoglobin, pretreatment calcium level, PS, time from diagnosis to onset of metasta‐ sis, and treatment-related hypertension, hypertension was an independent predictor of progression-free survival (*P* = 0.0030) [25].

Szmit et al. [26] reported that patients who developed hypertension related to sunitinib treatment experienced significantly longer progression-free survival time and overall sur‐ vival time compared to those who did not hypertension (*P*< 0.00001). Patients treated with at least 3 antihypertensive agents experienced significantly longer progression-free survival time (*P* = 0.00002) and overall survival time (*P* = 0.00001) compared either with patients who received one or two medications or with patients who received no medications [26].

Rixe et al. [27] reported that appearance or worsening hypertension was found to be the sin‐ gle independent predictor of a better clinical response to sunitinib on multivariate analysis using logistic regression model (*P* = 0.009). Furthermore, grade 3 hypertension was correlat‐ ed with a better outcome (*P* = 0.03). The appearance of hypertension, particularly grade 3, was associated with higher treatment response to sunitinib in metastatic renal tumors. Early and intensive antihypertensive therapy with the goal of maintaining the sunitinib use may improve response rate in those patients [27].

Overall, hypertension related to sunitinib was a positive predictive factor associated with significantly better objective response rate, longer progression-free survival and overall sur‐ vival in patients with metastatic renal tumor treated with sunitinib.

### *3.3.2. Hypothyroidism*

CRP is a significant independent prognostic indicator for patients with advanced renal tu‐ mor treated with sunitinib. Pretreatment CRP level could be a useful biomarker for response

Sunitinib has been related a variety of adverse events, key notable clinical adverse events included diarrhea (61%), fatigue (54%), hypertension (30%), stomatitis (30%), HFS (29%), and asthenia (20%) [4]. Laboratory abnormalities also found that included leukopenia (78%), anemia (79%), increased creatinine (70%), and thrombocytopenia (68%) [4]. If adverse events depends on the degree of systemic exposure to sunitinib, on which clinical efficacy also de‐ pends, adverse events might be potential predictors of sunitinib efficacy [21]. Several au‐ thors have described the correlation between sunitinib responses and selected treatment-

Hypertension is commonly associated with targeted therapy. It develops when VEGF stimu‐ lates production of nitric oxide and prostacyclins in vascular endothelial cells [22, 23], vaso‐ dilatory mechanisms become inhibited, and peripheral vascular resistance increases, leading

Rini et al. [24] demonstrated that sunitinib-associated hypertension is associated with im‐ proved clinical outcomes without clinically significant increases in hypertension-associated adverse events. This analysis included large pooled data from four clinical trilas of 4915 pa‐ tients with metastatic renal tumor who were treated with sunitinib. Sunitinib-induced hy‐ pertension had significantly better outcomes than those without treatment-induced hypertension in the objective response rate (54.8% *vs* 8.7%), the median progression-free sur‐ vival time (12.5 *vs* 2.5 months), and the median overall survival time (30.9 *vs* 7.2 months, *P*<

Bono et al. [25] reported that sunitinib-induced hypertension was associated with frequent tumor response (*P* = 0.001), significantly longer disease progression time (*P* = 0.0003), and overall survival time (*P* = 0.001). On multivariate analysis including the variables of pretreat‐ ment hemoglobin, pretreatment calcium level, PS, time from diagnosis to onset of metasta‐ sis, and treatment-related hypertension, hypertension was an independent predictor of

Szmit et al. [26] reported that patients who developed hypertension related to sunitinib treatment experienced significantly longer progression-free survival time and overall sur‐ vival time compared to those who did not hypertension (*P*< 0.00001). Patients treated with at least 3 antihypertensive agents experienced significantly longer progression-free survival time (*P* = 0.00002) and overall survival time (*P* = 0.00001) compared either with patients who

Rixe et al. [27] reported that appearance or worsening hypertension was found to be the sin‐ gle independent predictor of a better clinical response to sunitinib on multivariate analysis

received one or two medications or with patients who received no medications [26].

to sunitinib treatment [20].

38 Renal Tumor

**3.3. Selected adverse events**

related adverse events.

to increased blood pressure.

progression-free survival (*P* = 0.0030) [25].

*3.3.1. Hypertension*

0.001 for all) [24].

Treatment-related hypothyroidism has been reported a useful predictor of progression-free survival for metastatic renal tumors undergoing treatment with sunitinib [28]. In the 52 patients with metastatic renal tumor treated with sunitinib, 13 patients (25.0%) developed hypothyr‐ oidism during treatment. Subclinical hypothyroidism was defined as serum TSH above the upper limit of normal, with total triiodothyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Hypothyroidism was associated with a longer progression-free survival time (*P* = 0.032). Hormone replacement with 1-thyroxine did not have an influence on survival [28].

### **3.4. Others**

Han et al. [29] reported the initial tumor enhancement on contrast-enhanced computed to‐ mography (CT) could be useful as a clinical predictor during targeted therapy in 198 meta‐ static lesions of 46 patients. On multivariate analyses, tumor enhancement and enhancement pattern were associated with objective responses (*P* = 0.003 and 0.028, respectively). Addi‐ tionally, tumor enhancement was associated with tumor size reduction (*P* = 0.004). On Cox proportional hazards models, only tumor enhancement was associated significantly with the time to size reduction and progression-free survival time (*P* = 0.03 and 0.015, respective‐ ly). Tumor enhancement on contrast-enhanced CT was associated with tumor size reduc‐ tion, time to response, and time to progression of individual metastases in patients with metastatic renal tumor who received targeted therapy [29].

Kayani et al [30] revealed prognostic significance of 18F-fluorodeoxyglucose-positron emis‐ sion tomography (FDG-PET)/CT as a biomarker of response to sunitinib. A total of 44 pa‐ tients with newly diagnosed untreated metastatic renal tumor were enrolled in this study. 18F-FDG-PET/CT scans were conducted before, after 4 weeks, and after 16 weeks of sunitinib given. On multivariate analysis, a high SUVmax and an increased number of PET-positive le‐ sions correlated with shorter overall survival. The early metabolic responses are associated with a pharmacodynamic effect of drug and it is not until later identification with acquired resistance occurs [30].

Yuasa et al. [31] reported that initial tumor size is inversely associated with the tumor reduc‐ tion rate of individual metastatic sites and primary tumors in patients with metastatic renal tumor who underwent targeted therapy. A data from 139 metastatic and 16 primary lesions treated with targeted agents were analyzed. Both univariate and multivariate linear regres‐ sion analyses revealed that only the initial tumor size was associated with the rate of reduc‐ tion in individual tumors (*P*< 0.001) [31].

**Author details**

\*Address all correspondence to: tfujita@cd5.so-net.ne.jp

nal cell carcinoma. *JAMA*, 295(21), 2516-2524.

*New England Journal of Medicine*, 356(2), 115-124.

Department of Urology, Kitasato University School of Medicine, Japan

, Masatsugu Iwamura, Kazumasa Matsumoto and Kazunari Yoshida

Signaling Pathways and Biomarkers in Renal Tumors

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41

[1] Motzer, R. J, Michaelson, M. D, Redman, B. G, Hudes, G. R, Wilding, G, Figlin, R. A, Ginsberg, M. S, Kim, S. T, Baum, C. M, DePrimo, S. E, Li, J. Z, Bello, C. L, Theuer, C. P, George, D. J, & Rini, B. I. (2006). Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor recep‐ tor, in patients with metastatic renal cell carcinoma. *Journal of Clinical Oncology*, 24(1),

[2] Motzer, R. J, Rini, B. I, Bukowski, R. M, Curti, B. D, George, D. J, Hudes, G. R, Red‐ man, B. G, Margolin, K. A, Merchan, J. R, Wilding, G, Ginsberg, M. S, Bacik, J, Kim, S. T, Baum, C. M, & Michaelson, M. D. (2006). Sunitinib in patients with metastatic re‐

[3] Motzer, R. J, Hutson, T. E, Tomczak, P, Michaelson, M. D, Bukowski, R. M, Rixe, O, Oudard, S, Negrier, S, Szczylik, C, Kim, S. T, Chen, I, Bycott, P. W, Baum, C. M, & Figlin, R. A. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.

[4] Motzer, R. J, Hutson, T. E, Tomczak, P, Michaelson, M. D, Bukowski, R. M, Oudard, S, Negrier, S, Szczylik, C, Pili, R, Bjarnason, G. A, Garcia-del-Muro, X, Sosman, J. A, Solska, E, Wilding, G, Thompson, J. A, Kim, S. T, Chen, I, Huang, X, & Figlin, R. A. (2009). Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. *Journal of Clinical Oncology*,

[5] Uemura, H, Shinohara, N, Yuasa, T, Tomita, Y, Fujimoto, H, Niwakawa, M, Mugiya, S, Miki, T, Nonomura, N, Takahashi, M, Hasegawa, Y, Agata, N, Houk, B, Naito, S, & Akaza, H. (2010). A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. *Japanese Journal*

[6] Tomita, Y, Shinohara, N, Yuasa, T, Fujimoto, H, Niwakawa, M, Mugiya, S, Miki, T, Uemura, H, Nonomura, N, Takahashi, M, Hasegawa, Y, Agata, N, Houk, B, Naito, S, & Akaza, H. (2010). Overall survival and updated results from a phase II study of su‐ nitinib in Japanese patients with metastatic renal cell carcinoma. *Japanese Journal of*

Tetsuo Fujita\*

**References**

16-24.

27(22), 3584-3590.

*of Clinical Oncology*, 40(3), 194-202.

*Clinical Oncology*, 40(12), 1166-1172.

Abel et al. [32] reported that early 10% decrease in tumor diameter of the primary tumor was predictive of improved overall survival in patients with metastatic renal tumor treated with sunitinib. In 75 consecutive treatment-naive patients, median overall survival time for patients without minor primary tumor response, with minor primary tumor response after 60 days, and with early minor primary tumor response was 10.3, 16.5, and 30.2 months, re‐ spectively. On multivariate analysis, early minor response was an independent predictor of improved overall survival (*P* = 0.031) [32].

High visceral fat area could be a predictive biomarker from shorter survival in patients giv‐ en first-line antiangiogenic agents including sunitinib for metastatic renal tumors [33]. In 113 study population, 46 patients received sunitinib as first-line therapy. Visceral fat area was measured retrospectively on the available CT scans performed before sunitinib initiation at the level of the umbilicus with the patient in the supine position. ImageJ software was used to measure pixels with densities in the -190 Hounsfield units to -30 Hounsfield units range to delineate the visceral compartment and to compute the cross-sectional area of each in cm2 . On multivariate analysis, high visceral fat area was independently associated with shorter time to progression and overall survival. Visceral fat area measured before starting first-line targeted therapy is likely to be a simple predictive biomarker in patients with metastatic re‐ nal tumor [33].

Finally, hyponatremia seem to represent significant predictive factor for cancer-specific sur‐ vival in metastatic renal tumors treated with targeted therapy as first-line therapy [34]. A total of 87 patients treated with targeted therapy including sunitinib, severe (≤ 134 mEq/L) and mild (135-137 mEq/L) hyponatremia was shown to be significantly associated with can‐ cer-specific survival time (*P* = 0.001 and 0.013, respectively). In 38 patients treated wth suni‐ tinib, 4 patients (10.5%) developed severe hyponatremia and 8 patients (21.1%) developed mild hyponatremia. Hyponatremia could be easily and readily determined and might be an important prognostic factor [34].

### **4. Conclusions**

Candidate biomarkers to predict response to sunitinib have been shown. Among clinical factors, CRP is a significant independent prognostic indicator for sunitinib. Severe adverse events, hypertension and hypothyroidism also recognized as biomarkers of favorable efficacy. Addi‐ tionally, tumor enhancement, SUVmax on FDG/PET-CT, tumor size, visceral fat area and hypo‐ natremia have been revealed clinical significance of sunitinib responses. Although further investigation will be required, these biomarkers can be utilized to measure therapeutic re‐ sponse and design treatment strategies for advanced renal tumors treated with sunitinib.
