Maya Ish-Shalom

Pretreatment Neutrophil-to-Lymphocyte Ratio in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Ketoconazole: Association with Outcome and Predictive Nomogram

BACKGROUND The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole. METHODS This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis. RESULTS Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups. CONCLUSIONS In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.

Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma

BACKGROUND Bisphosphonates are used to prevent skeletal events of bone metastases, and may exhibit antitumour effects. We aimed to evaluate whether bisphosphonates can bring a response rate (RR), progression free survival (PFS) and overall survival (OS) benefit to patients with bone metastasis from renal cell carcinoma (RCC) that is treated with sunitinib. METHODS We performed a multicentre retrospective study of patients with bone metastases from RCC that was treated with sunitinib. The effect of bisphosphonates on RR, PFS and OS was tested with adjustment for known prognostic factors using a chi-square test from contingency table and partial likelihood test from Cox regression model. RESULTS Between 2004 and 2011, 209 patients with metastatic RCC were treated with sunitinib, 76 had bone metastases, 35 bisphosphonates users and 41 non-users. The groups of bisphosphonates users and non-users were balanced regarding known prognostic factors. Objective response was partial response/stable disease 86% (n = 30) versus 71% (n = 29), and progressive disease 14% (n = 5) versus 29% (n = 12) (p = 0.125, OR 2.48) in users versus non-users, respectively. Median PFS was 15 versus 5 months (HR = 0.55, p<0.0001), and median OS was not reached (with a median follow-up time of 45 months) versus 14 months (HR = 0.4, p = 0.029), in favour of users. In multivariate analysis of the entire patient cohort (n = 76), factors associated with PFS were bisphosphonates use (HR = 0.58, p = 0.035), and pre-treatment neutrophil to lymphocyte ratio >3 (HR = 3.5, p = 0.009). Factors associated with OS were bisphosphonates use (HR = 0.5, p = 0.008), elevated pre-treatment alkaline phosphatase (HR = 2.9, p = 0.003) and sunitinib induced HTN (HR = 0.63, p<0.0001). CONCLUSIONS Bisphosphonates may improve the RR, PFS and OS of sunitinib treatment in RCC with bone metastases.

Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

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.

Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases

One third of patients with metastatic renal cell carcinoma (RCC) suffer from bone metastases. Skeletal involvement in RCC is associated with the occurrence of skeletal-related events, and may negatively impact on the outcome of patients treated with systemic therapies. In patients with RCC and bone metastases, therapies that inhibit osteoclasts, as bisphosphonates and denosumab, are used as adjunct to systemic targeted therapies to prevent skeletal-related events. Data suggest that they may also improve the outcome of systemic targeted therapies. Herein we review the preclinical and clinical data on their use, as well as remaining open questions.

Pretreatment (pre-tx) neutrophil to lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with ketoconazole (keto): Association with outcome and predictive model.

37 Background: The CYP17 inhibitor Keto is active in mCRPC. The NLR, an index of systemic inflammation, is associated with prognosis in several types of cancer. We assessed the association between pre-tx NLR and outcome of mCRPC pts treated with keto. METHODS We performed a multicenter retrospective study of pts with mCRPC, who were treated with keto. We analyzed the pre-tx NLR and previously described factors associated with keto tx outcome as prior response to hormonal tx, pre-tx PSADT, and extent of metastatic disease (limited-axial skeleton/nodal vs extensive- appendicular skeleton/visceral). Progression free survival (PFS) was determined by the Kaplan-Meier method. Multivariate analyses using Cox regression model were performed to determine their independent effect, and to form a predictive model. A survival tree analysis was used to find the best NLR cut-off value. RESULTS From 1999-2011, 135 mCRPR pts were treated with keto. 67/135 (50%) had ≥ 50% PSA decline. Overall median PFS was 8 months (mos) (range 1-134 ). Excluded from the analysis were pts without available data on pre-tx NLR (n=8), and those with recent (≤1 mos) health event (surgery, n=1) or tx (steroids, n=3 or radiation, n=3) known to be associated with a change of blood counts. 120 pts were included in the analysis. 57 (48%) had an elevated pre-tx NLR >3. Risk factors associated with PFS (table) were pre-tx NLR >3, prior response to GnRH-a <24 mos and to AA <6 mos, and pre-tx PSADT <3 mos. The number of risk factors was used to categorize patients into three risk groups (table): favorable (0-1 factors), intermediate (2 factors), and poor (3-4 factors). CONCLUSIONS In mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, and pre-tx PSADT are associated with PFS, and may be used to categorize pts into risk groups. [Table: see text].

Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease treated with sunitinib.

437 Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC. METHODS We performed a multicentre retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese=BMI≥30 vs overweight=BMI 25-29.9 vs normal weight=BMI <25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to Su tx, > 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level > 10 mg/dL, elevated alkaline phosphatase (AP), platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and mean Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect. RESULTS Between 2004-2011, 209 pts with mRCC were treated with Su. 40 pts were active smoker, 51 obese, 55 diabetic, and 122 had pre-tx HTN. In the entire pt cohort, median PFS was 8 months (mos) and OS 15 mos. Factors associated with PFS were active smoking (HR 2.5, p= 0.005, median PFS 4 vs 10 mos in past smokers vs 10 mos in never smokers), non clear cell histology (HR 1.8, p=0.023), pre-tx NLR >3 (HR 0.2, p<0.0001) and the use of ASIs (HR 1.66, p=0.028). Factors associated with OS were were active smoking (HR 2.1, p= 0.03, median OS 8.5 vs 18 mos in past smokers vs 18 mos in never smokers), AP (HR 1.76, p=0.049), pre-tx NLR >3 (HR 0.294, p<0.0001), and liver mets (HR 0.553, p=0.04). BMI, DM, and pre-tx HTN were not associated with PFS or OS. CONCLUSIONS Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

Effect of bisphosphonates (Bis) combined with sunitinib (Su) on the response rate (RR), progression-free survival (PFS), and overall survival (OS) of patients (pts) with bone metastases (mets) from renal cell carcinoma (RCC).

379 Background: Bis are used to prevent skeletal events of bone mets, and may exhibit anti tumor effects. We aimed to evaluate whether Bis can bring a RR, PFS, and OS benefit to pts with bone mets from RCC that are treated with Su. METHODS We performed a multicentre retrospective study of pts with bone mets from RCC who were treated with Su. Pts were divided into Bis users (group 1) and nonusers (group 2). The effect of Bis on RR, PFS and OS, was tested with adjustment for known prognostic factors using a chisquare test from contingency table and partial likelihood test from Cox regression model. RESULTS Between 2004-2011, 209 pts with metastatic RCC were treated with Su. 76 pts had bone mets, 35 group 1 and 41 group 2. The groups were balanced regarding the following known prognostic factors: past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to sunitinib treatment (tx), the presence of > 2 mets sites, the presence of lung/liver mets, ECOG performance status, anemia, calcium level >10 mg/dL, elevated alkaline phosphatase, platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, sunitinib induced HTN, and the use of angiotensin system inhibitors. They were also balanced with regard to past cytokines/targeted tx, and mean sunitinib dose/cycle. Objective response was partial response/stable disease 86% (n=30) vs 71% (n=29), and progressive disease 14% (n=5) vs 29% (n=12) (p=0.125, OR 2.48) in group 1 vs 2 respectively. Median PFS was 15 vs 5 months (HR 2.6, p < 0.0001), and median OS 21 vs 13 months (HR 2.1, p=0.029), in favor of group 1. In multivariate analysis of the entire pt cohort (n=76), factors associated with PFS were Bis use (HR 2.2, p=0.035) and pre-tx NLR >3 (HR 0.38, p=0.009). Factors associated with OS were Bis use (HR 2.8, p=0.008), elevated alkaline phosphatase level (HR 0.287, p=0.0003), and Su induced HTN (HR 5.57, p < 0.0001). CONCLUSIONS Bis may improve the outcome of Su tx in RCC with bone mets. Whether this is generalizable to other TKIs is not known. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

The Proatherogenic Effect of Chronic Nitric Oxide Synthesis Inhibition in ApoE-Null Mice Is Dependent on the Presence of PPARα

Inhibition of endothelial nitric oxide synthase (eNOS) accelerates atherosclerosis in ApoE-null mice by impairing the balance between angiotensin II (AII) and NO. Our previous data suggested a role for PPARα in the deleterious effect of the renin-angiotensin system (RAS). We tested the hypothesis that ApoE-null mice lacking PPARα (DKO mice) would be resistant to the proatherogenic effect of NOS inhibition. DKO mice fed a Western diet were immune to the 23% worsening in aortic sinus plaque area seen in the ApoE-null animals under 12 weeks of NOS inhibition with a subpressor dose of L-NAME, P = 0.002. This was accompanied by a doubling of reactive oxygen species (ROS-) generating aortic NADPH oxidase activity (a target of AII, which paralleled Nox1 expression) and by a 10-fold excess of the proatherogenic iNOS, P < 0.01. L-NAME also caused a doubling of aortic renin and angiotensinogen mRNA level in the ApoE-null mice but not in the DKO, and it upregulated eNOS in the DKO mice only. These data suggest that, in the ApoE-null mouse, PPARα contributes to the proatherogenic effect of unopposed RAS/AII action induced by L-NAME, an effect which is associated with Nox1 and iNOS induction, and is independent of blood pressure and serum lipids.

Are there geographic differences in the outcome of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (su)

458 Background: Geographic differences in the outcome of pts have been described in various cancers. The VEGFR inhibitor su is a standard treatment (tx) for mRCC. The effect of geographic differences on the outcome of su tx in mRCC is poorly defined. We aimed to study the effect of geographic differences on outcome of su tx in mRCC. METHODS We performed an international multicenter retrospective study of unselected cohort of 275 mRCC pts, who were treated with su from 2004 to 2012 in 7 centers across the United States and Middle East (ME; Israel). Clinicopathologic and prognostic factors, and tx outcome were compared between United States (n=133) and ME (n=142) pts. Chi-square and Fishers exact tests were used to compare categorical variables, and two-sample t-test was used to compare continuous endpoints. Progression free survival (PFS) and overall survival (OS) were determined by Cox regression. RESULTS Median age was 61 (United States) vs. 65 (ME, p = 0.01). The groups were balanced regarding gender, Heng risk, past nephrectomy, RCC histology, presence of ≥ 2 metastatic sites, lung/liver/bone metastasis, use of angiotensin system inhibitors (ASI), prior cytokines/ targeted txt, su induced HTN, and su dose reduction/tx interruption secondary to side effects. The incidence of active smokers (28% vs. 15%, p =0.01), bisphosphonates users (23% vs. 13%, p = 0.03) and pts with pre-tx neutrophil to lymphocyte ratio (NLR) ≤ 3 (63% vs. 49%, p = 0.04) was higher among ME pts. In United States vs. ME pts, objective response was partial response/stable disease 77% (n=102) vs. 79% (n=112), and progressive disease at first imaging evaluation within the first 3 months (mos) 23% (n=31) vs. 21% (n=30) (p = 0.77, OR 1.1). Median PFS was 8 vs. 12 mos (HR=1.8, p < 0.0001), and median OS 21 vs. 22 mos (HR=0.94, p = 0.9) in United States vs ME pts. Factors associated with PFS in multivariate analysis of the entire cohort (n=275) were geographic location (United States vs. ME), Heng risk, RCC histology, su induced HTN, ASI use, pre-tx NLR, and smoking status. CONCLUSIONS Geographic differences in clinicopathologic factors and PFS of pts with mRCC treated with su may exist. This should be further investigated, and if validated, applied in clinical practice and clinical trials.

Is there a "trial effect" on outcome of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib?

453 Background: Several studies have suggested the existence of a trial effect, in which for a given treatment, participation in a clinical trial is associated with a better outcome of cancer patients. The VEGFR inhibitor sunitinib is a standard treatment for mRCC. The effect of clinical trial participation on the outcome of sunitinib treatment in mRCC is poorly defined. We aimed to study the effect of clinical trial participation on outcome of mRCC patients treated with sunitinib. METHODS Records from 275 mRCC patients treated with sunitinib from 2004 to 2012 in 7 centers across 2 countries were reviewed. We compared the response rate, progression free survival, and overall survival, between clinical trial participants (n=49) and a matched cohort of non participants (n=49) who received standard therapy. Each patient participating in a clinical trial was individually matched with a non-participant by clinicopathologic factors. Progression free survival and overall survival were determined by Cox regression. RESULTS The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 24%, intermediate 60%, poor 16%), ECOG performance status (0-1 92%), prior nephrectomy (92%), renal cell carcinoma histology (clear cell 80%), sunitinib induced hypertension (56%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants vs. non participants, objective response was partial response/stable disease 80% (n=39) vs. 73% (n=36), and progressive disease at first imaging evaluation within the first 3 months (mos) 20% (n=10) vs. 27% (n=13) (p = 0.63, OR 1.2). Median progression free survival was 10 vs. 11 mos (HR=0.96, p = 0.84), and median overall survival 23 vs. 24 mos (HR=0.97, p=0.89). CONCLUSIONS In mRCC patient treated with sunitinib, the outcome of clinical trial participants was similar to matched non participants who received standard therapy.