Ali Reza Golshayan

Prognostic Factors for Overall Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor–Targeted Agents: Results From a Large, Multicenter Study

PURPOSE There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. METHODS Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. RESULTS The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. CONCLUSION This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.

Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients

Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor cells (MDSC) represent one mechanism by which tumors induce T-cell suppression. Several factors pivotal to the accumulation of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression in RCC patients has been investigated. Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-γ were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-γ were examined. The in vitro effect of sunitinib on patient MDSC was evaluated. Results: Metastatic RCC patients had elevated levels of CD33+HLA-DR− and CD15+CD14− MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of MDSC in vitro. MDSC reduction in response to sunitinib correlated with a reversal of CD3+CD4+CD25hiFoxp3+ Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-γ. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at ≥1.0 μg/mL. Sunitinib did not induce MDSC maturation in vitro. Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.

Sunitinib Reverses Type-1 Immune Suppression and Decreases T-Regulatory Cells in Renal Cell Carcinoma Patients

Purpose: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T-cell cytokine response and enhanced T-regulatory (Treg) cell expression. Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it is relevant to assess their effect on the immune system. Experimental Design: Type-1 (IFNγ) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib (50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies. Results: After one cycle of treatment, there was a significant increase in the percentage of IFNγ-producing T cells (CD3+, P < 0.001; CD3+CD4+, P = 0.001), a reduction in interleukin-4 production (CD3+ cells, P = 0.05), and a diminished type-2 bias (P = 0.005). The increase in type-1 response may be partly related to modulation of Treg cells. The increased percentage of Treg cells noted in mRCC patients over healthy donors (P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation between the increase in type-1 response after two cycles of treatment and a decrease in the percentage of Treg cells (r = −0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib on Treg cells are indirect. Conclusions: The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducing Treg function provides a basis for the rational combination of sunitinib and immunotherapy in mRCC.

Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy

Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care for patients with metastatic renal cell carcinoma (RCC). The identification of patients who are more likely to benefit from these agents is warranted.

von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma

PURPOSE The von Hippel-Lindau (VHL) gene is often inactivated (by mutation or promoter hypermethylation) in renal cell carcinoma but the relation to therapeutic outcome is unclear. MATERIALS AND METHODS Patients with metastatic clear cell renal cell carcinoma with available baseline tumor samples who received vascular endothelial growth factor targeted therapy were included in analysis. Patient characteristics, VHL gene status and clinical outcome were documented. Our primary end point was to test for response rate in relation to VHL inactivation. Progression-free survival and overall survival in relation to VHL status were investigated as secondary end points. RESULTS A total of 123 patients were evaluable. Response rate, median progression-free survival and median overall survival were 37% (95% CI 28-46), 10.8 (95% CI 7.7-14.8) and 29.8 (CI not estimable) months, respectively. Patients with VHL inactivation had a response rate of 41% vs 31% for those with wild-type VHL (p = 0.34). Patients with loss of function mutations (frameshift, nonsense, splice and in-frame deletions/insertions) had a 52% response rate vs 31% with wild-type VHL (p = 0.04). On multivariate analysis the presence of a loss of function mutation remained an independent prognostic factor associated with improved response. Progression-free survival and overall survival were not significantly different based on VHL status. CONCLUSIONS To our knowledge this is the largest analysis investigating the impact of VHL inactivation on the outcome of vascular endothelial growth factor targeted agents in metastatic renal cell carcinoma. We did not find a statistically significant increase in response to vascular endothelial growth factor targeted agents in patients with VHL inactivation. Loss of function mutations identified a population of patients with a greater response. Investigation of downstream markers is under way.

Metastatic Sarcomatoid Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor–Targeted Therapy

PURPOSE Metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation is an aggressive disease that is associated with poor outcomes to chemotherapy or immunotherapy. The utility of vascular endothelial growth factor (VEGF)-targeted therapy in patients with this disease is unknown. PATIENTS AND METHODS Patients who had mRCC with sarcomatoid features in the primary tumor and who were treated with VEGF-targeted therapy were retrospectively identified. Pathology slides were reviewed to determine the percentage of sarcomatoid differentiation. Objective response rate, percentage of tumor burden shrinkage, progression-free survival (PFS), and overall survival (OS) were determined. RESULTS Forty-three patients who had sarcomatoid mRCC were identified. The median percentage of sarcomatoid features was 14% (range, 3% to 90%). Patients were treated with either sunitinib (49%), sorafenib (28%), bevacizumab (19%), or sunitinib plus bevacizumab (5%). Partial responses were observed in eight patients (19%); 21 patients (49%) had stable disease; and 14 patients (33%) had progressive disease as their best response. Partial responses were limited to patients who had underlying clear-cell histology and less than 20% sarcomatoid elements. Median tumor shrinkage was -2% (range, -85% to 127%), and 53% achieved some degree of tumor shrinkage on therapy. Median PFS and OS were estimated to be 5.3 months and 11.8 months, respectively. CONCLUSION Patients who have mRCC and sarcomatoid differentiation can demonstrate objective responses and tumor shrinkage to VEGF-targeted therapy. Patients who have clear-cell histology and a lower percentage of sarcomatoid differentiation may have better outcomes with VEGF-targeted therapy.

Efficacy of growth factors compared to other therapies for low-risk myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) represent a heterogeneous group of disorders. Low‐risk MDS represent a subgroup with a relatively good prognosis, but with few trials evaluating outcomes. A pooled analysis based upon a MEDLINE search identified 162 original articles describing patient characteristics and effect of therapy on 2592 individuals with pathologically confirmed refractory anaemia or refractory anaemia with ringed sideroblasts with <5% bone marrow blasts. Treatments were categorised as growth factors (GF) or non‐growth factors (NGF). International Prognostic Scoring System (IPSS) score was documented or calculated when possible. Responses and outcomes were standardised according to the International Working Group MDS criteria. Growth factors produced higher overall response rates (39·5% vs. 31·4% for NGF, P = 0·019), while NGF yielded better CR/PR rates (25·6% vs. 9·1% for GF, P = 0·03). Over 2 years of follow‐up, those receiving GF demonstrated greater overall and progression‐free survival than NGF, after controlling for baseline patient characteristics. Decision tools need to be developed to determine which therapy to choose for patients with low‐risk MDS.

Sunitinib and sorafenib in metastatic renal cell carcinoma patients with renal insufficiency

BACKGROUND Although clinical trials with sunitinib and sorafenib in metastatic renal cell carcinoma (mRCC) have included patients with moderate renal insufficiency (RI), the incidence of renal toxicity induced by their administration as well as the safety of these agents in patients with more severe renal insufficiency has not been extensively reported. PATIENTS AND METHODS Patients with mRCC treated with vascular endothelial growth factor-targeted therapy with either RI at time of treatment initiation or who developed RI during therapy were identified. RI was defined as serum creatinine (Cr) > or = 1.9 mg/dl or a creatinine clearance (CrCl) < 60 ml/min/1.73 m(2) for >3 months before treatment. Objective outcomes and toxic effects of treatment were also measured. RESULTS A total of 39 patients were identified: 21 patients who initiated therapy with preexisting RI and 18 patients who developed RI during treatment. In patients with RI at the start of therapy, Cr increased in 57%, and 48% of patients required dose reduction. The median time to maximum RI was 6.6 months (range 0.4-19.6 months). In patients who developed RI while receiving therapy, median serum Cr and CrCl at the start of therapy were 1.5 mg/dl (range 1.1-1.8) and 61 ml/min (range 43-105), respectively. Patients experienced a median increase in serum Cr of 0.8 mg/dl (range 0.3-2.8) and a median decrease in CrCl of 25 ml/min (range 8.54-64.76). Overall, 5 patients (24%) achieved a partial response (PR), 13 (62%) had stable disease (SD) and 3 (14%) had progressive disease (PD). Estimated progression-free survival (PFS) was 8.4 months. The most common toxic effects (all grades) were fatigue (81%), hand-foot syndrome (HFS) (52%) and diarrhea (48%). Six patients experienced grade III toxicity (29%), primarily HFS. CONCLUSIONS Sunitinib and sorafenib can be safely given to patients with renal insufficiency, provided adequate monitoring of renal function. For those patients developing an increase in Cr, dose modifications may be required to allow continuation of therapy. The clinical outcome of patients with baseline renal dysfunction and patients who develop renal dysfunction does not appear to be compromised.

A decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are divided into low‐risk and high‐risk diseases. Predictive models for response to growth factors (GF) have been developed based on red blood cell transfusion needs and erythropoietin levels. For low‐risk MDS the optimal initial therapy (GF vs nongrowth factor [NGF] therapies, including differentiation and immunomodulatory agents) based on response rates to NGF and GF and survival, has not been defined.

Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer.

Introduction Enzalutamide is an oral androgen receptor (AR) signaling inhibitor that was specifically engineered to overcome castration-resistant prostate cancer (CRPC) harboring AR amplification or overexpression. Enzalutamide has demonstrated significant activity in men with metastatic CRPC. Aims To update the evidence and provide an overview of the available data on enzalutamide. Evidence review Peer reviewed articles published and listed in Medline Search were reviewed. In addition, relevant ASCO and ESMO abstracts were searched. The activity of enzalutamide is mediated by potently antagonizing the full-length AR, impairing translocation of the AR from the cytoplasm into the nucleus, and inhibiting the transcriptional activity of the AR by modulating the interaction of the AR with androgen-response elements in gene promoter regions. Enzalutamide has a favorable safety profile and the most common adverse events include fatigue, hot flashes and headache; 1% of patients experienced seizure. Place in Therapy The AFFIRM phase III study evaluated the clinical utility of treatment with enzalutamide in men with docetaxel-refractory metastatic CRPC. Enzalutamide improved overall survival compared to placebo, with a median overall survival of 18.4 months versus 13.6 months respectively. Conclusion Enzalutamide has demonstrated impressive efficacy in men with metastatic CRPC, moving swiftly from a phase I/II study to two pivotal phase III trials testing this agent in both chemotherapy-pretreated as well as chemotherapy-naïve CRPC patients. Ongoing studies are aiming to explore the utility of enzalutamide in earlier stages of the disease, and to investigate the optimal sequencing and combination of enzalutamide with other standard and novel therapies for prostate cancer.