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Background: Limited data about biomarkers are available to predict the outcomes of targeted therapy in metastatic renal cell carcinoma (mRCC). Circulating cell-free DNA (CFD) is elevated in various cancers., Patients and Methods: We performed a prospective study of patients with mRCC who received targeted therapy in the Soroka Medical Center between 2013 and 2015. CFD levels were measured using a simple fluorometric assay. Blood samples for CFD were collected before treatment and at weeks 1, 4, 12, 18, and 24 of treatment. The normal cut-off level of CFD was defined as 800 ng/ml. The association of CFD with objective response, progression-free survival (PFS), and overall survival was tested, with adjustment for known confounding risk factors., Results: A total of 23 patients were included; 18 were treated with first-line therapy and 5 with second- and third-line therapies. Patients with normal pretreatment CFD level had a better PFS versus patients with increased levels (p = 0.023). In multivariate analysis, factors associated with PFS were pretreatment CFD levels (p = 0.020) and Heng risk (p = 0.006)., Conclusions: Elevated pretreatment CFD levels measured using a simple fluorometric assay may be associated with a worse PFS in patients with mRCC. A larger prospective study is warranted in order to validate our observation., (© 2017 S. Karger GmbH, Freiburg.)

Background: Although studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC., Patients and Methods: We performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort., Results: Between 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio > 3. Factors associated with OS were metformin use (hazard ratio, 0.21; P < .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio > 3., Conclusion: Metformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sunitinib is a standard treatment for metastatic clear cell renal cell carcinoma (mccRCC). Data on its activity in the rare variant of metastatic chromophobe renal cell carcinoma (mchRCC), are limited. We aimed to analyze the activity of sunitinib in a relatively large and homogenous international cohort of mchRCC patients in terms of outcome and comparison with mccRCC., Methods: Records from mchRCC patients treated with first-line sunitinib in 10 centers across 4 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and outcome were performed. Subsequently, mchRCC patients were individually matched to mccRCC patients. We compared the clinical benefit rate, progression-free survival (PFS), and overall survival (OS) between the groups., Results: Between 2004 and 2014, 36 patients (median age, 64 years; 47% male) with mchRCC were treated with first-line sunitinib. Seventy-eight percent achieved a clinical benefit (partial response + stable disease). Median PFS and OS were 10 and 26 months, respectively. Factors associated with PFS were the Heng risk (hazard ratio [HR], 3.3; p = .03) and pretreatment neutrophil-to-lymphocyte ratio (NLR) >3 (HR, 0.63; p = .02). Factors associated with OS were the Heng risk (HR, 4.1; p = .04), liver metastases (HR, 3.8; p = .03), and pretreatment NLR <3 (HR, 0.55; p = .03). Treatment outcome was not significantly different between mchRCC patients and individually matched mccRCC patients. In mccRCC patients (p value versus mchRCC), 72% achieved a clinical benefit (p = .4) and median PFS and OS were 9 (p = .6) and 25 (p = .7) months, respectively., Conclusion: In metastatic chromophobe renal cell carcinoma, sunitinib therapy may be associated with similar outcome and toxicities as in metastatic clear cell renal cell carcinoma. The Heng risk and pretreatment NLR may be associated with PFS and OS., Implications for Practice: Data on the activity of sunitinib in metastatic chromophobe renal cell carcinoma (mchRCC) are limited. This study analyzed the activity of sunitinib in a cohort of mchRCC patients. Of 36 patients with mchRCC who were treated with first-line sunitinib, 78% achieved a clinical benefit. Median PFS and OS were 10 and 26 months, respectively. Treatment outcome was not significantly different between mchRCC patients and individually matched metastatic clear cell RCC patients., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

Purpose: Studies suggested the existence of a 'trial effect', in which for a given treatment, participation in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined., Materials and Methods: The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression., Results: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 25%, intermediate 59%, poor 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment NLR (>3 in 55%, n=27), sunitinib induced hypertension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63, OR 1.2). The median PFS was 10 versus 11 months (HR=0.96, p=0.84), and the median OS 23 versus 24 months (HR=0.97, p=0.89)., Conclusions: In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy.

Background: The VEGFR/PDGFR inhibitor sunitinib was approved in Israel in 2008 for the treatment of metastatic renal cell carcinoma (mRCC), based on an international trial. However, the efficacy of sunitinib treatment in Israeli mRCC patients has not been previously reported., Objectives: To report the outcome and associated factors of sunitinib treatment in a large cohort of Israeli mRCC patients., Methods: We conducted a retrospective study of an unselected cohort of mRCC patients who were treated with sunitinib during the period 2006-2013 in six Israeli hospitals. Univariate and multivariate analyses were performed to determine the association between treatment outcome and clinicopathologic factors., Results: We identified 145 patients; the median age was 65 years, 63% were male, 80% had a nephrectomy, and 28% had prior systemic treatment. Seventy-nine percent (n = 115) had clinical benefit (complete response 5%, n = 7; partial response 33%, n = 48; stable disease 41%, n = 60); 21% (n = 30) were refractory to treatment. Median progression-free survival (PFS) was 12 months and median overall survival 21 months. Factors associated with clinical benefit were sunitinib-induced hypertension: [odds ratio (OR) 3.6, P = 0.042] and sunitinib dose reduction or treatment interruption (OR 2.4, P = 0.049). Factors associated with PFS were female gender [hazard ratio (HR) 2, P = 0.0041, pre-sunitinib treatment neutrophil-to-lymphocyte ratio < or = 3 (HR 2.19, P = 0.002), and active smoking (HR 0.19, P < 0.0001). Factors associated with overall survival were active smoking (HR 0.25, P < 0.0001) and sunitinib-induced hypertension (HR 0.48, P = 0.005). To minimize toxicity, the dose was reduced or the treatment interrupted in 39% (n = 57)., Conclusions: The efficacy of sunitinib treatment for mRCC among Israeli patients is similar to that in international data.

Background: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC)., Methods: An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors., Results: Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002)., Conclusion: Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Interleukin-2 (IL-2) has some antitumor activity in patients with renal cell carcinoma. It has been noted that response to IL-2 and prognosis may be adversely affected by elevated serum levels of C-reactive protein (CRP) or interleukin-6 (IL-6). We used thalidomide to treat patients with cancer-induced cachexia and noted that the drug significantly reduced serum levels of CRP and IL-6 to normal or near normal levels in a substantial fraction of patients. We tested whether thalidomide might potentiate the response of patients with renal cell carcinoma to IL-2. Four patients with metastatic renal cell carcinoma and high serum levels of CRP and IL-6 who had experienced disease progression on IL-2 were retreated with the same IL-2 regimen combined with thalidomide 300 mg p.o. daily. Two patients achieved good partial responses and 2 patients had prolonged disease stabilization with the combination of IL-2 plus thalidomide. The regimen was well tolerated without increased IL-2-associated toxicity. Reduction of serum CRP or IL-6 levels with thalidomide may enhance the responsiveness of renal cell carcinoma to IL-2. A Phase II study of the combination is in order. It is possible that the thalidomide-induced normalization of serum acute phase proteins might improve the response of other types of malignancy to IL-2 or other immune-based therapies., (Copyright 2004 Wiley-Liss, Inc.)

Objective: Aim of this study was to analyze the prognostic value of age in patients with renal cell carcinoma (RCC)., Patients and Methods: A group of 15 patients (age < or = 40 years, group I) and a group of 103 patients (age > or = 50 years, group II) with sporadic RCC who underwent radical nephrectomy between 1985 and 1997 were compared. The two groups were analyzed with respect to histologic cell type, tumor grade, stage and outcome., Results: In group I low-stage tumors (stage I and II) were diagnosed in 93% of patients and in group II in 65% of the patients (p = 0.017). High-grade tumors (stage III and IV) were diagnosed in 7% and 35% of patients in group I and group II, respectively (p < 0.01). In group I only one patient (7%) with stage II disease died of cancer. In group II the distribution of cancer-specific mortality was as follows: 6 patients (100%) with stage IV, 13 patients (42%) with stage III, and 12 patients (17%) with stage I and II died of disease. The 5-year-survival in group I was 93% and in group II was 77% (p = 0.05)., Conclusion: According to our data we conclude that RCC is diagnosed at a lower stage in young patients than in the older patient group. RCC may exhibit a more favorable prognosis in young patients, possible due to the lower stage at time of diagnosis., (Copyright 2002 S. Karger GmbH, Freiburg)