A multiple endpoint approach reveals potential in vitro anticancer properties of thymoquinone in human renal carcinoma cells.

Thymoquinone (TQ) is a monoterpene isolated from the oil of Nigella sativa seeds. The aim of this work was to evaluate the cytotoxic effects induced by TQ and its impact on the migration and invasion potential of 786-O human renal cancer cells. These cells were exposed to TQ (1-100 µM) for 24 and 48 h and cell viability assessed using the Crystal Violet and MTS assays. TQ treatment clearly decreased cell viability in a concentration- and time-dependent manner. TQ exposure moderately increased intracellular ROS levels and co-incubation with reduced glutathione markedly increased cell viability. Moreover, the effect of TQ in the cell cycle distribution was evaluated using flow cytometry, and an increase in the sub-G1 population was observed, especially at 30 µM, along with an increase in the % of apoptotic cells. TQ did not show genotoxic effects at a non-cytotoxic concentration (1.0 µM). At this concentration level, TQ significantly decreased the collective migration of 786-O cells, whereas it had no effect in chemotactic migration. TQ also decreased the invasiveness potential of 786-O cells, as evaluated by the transwell invasion assay. Overall, these results suggest that TQ presents an anticancer potential in the context of renal cancer, warranting further investigation.

Sunitinib versus sorafenib for patients with advanced renal cell carcinoma with renal impairment before the immune-oncology therapy era.

OBJECTIVES: The efficacy and safety of sunitinib versus sorafenib in patients with advanced renal cell carcinoma with renal impairment remains poorly documented. PATIENTS AND METHODS: We assessed the efficacy and safety of sunitinib and sorafenib in patients with advanced renal cell carcinoma with an estimated glomerular filtration rate of 15-60 mL/min/1.73 m2 by reviewing the medical records of patients treated at Jichi Medical University Hospital, Japan, between May 2008 and August 2016. RESULTS: Twenty-seven patients were treated with sunitinib and 14 with sorafenib. Median progression-free survival in sunitinib- and sorafenib-treated patients was comparable, at 6.6 vs 5.8 months, respectively (HR, 1.618; 95% CI, 0.689-3.798; P = 0.2691). Median overall survival was also comparable, at 65.9 vs 58.0 months (HR, 0.985; 95% CI, 0.389-2.479; P = 0.9748). Grade 3 or higher adverse events were significantly more frequent in the sunitinib-treated than sorafenib-treated patients (P = 0.0357). Compared to pre-treatment values, estimated glomerular filtration rate at the discontinuation of treatment was not decreased in either group. In contrast, estimated glomerular filtration rate was decreased on long-term treatment, particularly in previously nephrectomized patients. CONCLUSIONS: Sunitinib and sorafenib had similar efficacy in patients with advanced renal cell carcinoma and severe renal impairment. Although renal function was not markedly impaired in either group, close attention to decreased renal function may be necessary in previously nephrectomized patients on long-term treatment.

Drug-Induced Hypertension Caused by Multikinase Inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in Renal Cell Carcinoma Treatment.

This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role.

Thymoquinone attenuates phosphorylation of AKT to inhibit kidney cancer cell proliferation.

Thymoquinone (Tq) is an active compound from Nigella sativa which is used in traditional medicine. The effect of Tq on kidney cancer and the pathway of action remain unproven. Herein, we report the anticancer properties of Tq on kidney cancer cells. Tq demonstrated anti-proliferative effects in A498 cells with a GI50 value of 40.07 µM and Caki-1 cells with a GI50 of 51.04 µM by the MTT assay. Tq exhibited nuclear fragmentation and inhibited trans-endothelial migration of A498 and Caki-1 cells in a dose-responsive manner. Time-dependent increase in Annexin V-positive cells and sub-G0 /G1 cell population was observed post-Tq treatment. The compound increased Bax protein levels and reduced Bcl-2 protein levels dose dependently in cells, thereby favoring apoptosis. Tq decreased the phosphorylation of Akt in both kidney cell types. The results suggest effective anticancer activity of Tq on kidney cancer cells which may be mediated by the Akt pathway. PRACTICAL APPLICATIONS: Results from the current investigation will through more light on the mechanistic pathway of Tq activity on the inhibition of kidney cancer cell proliferation. The output of this preclinical in vitro study may be translated into better chemotherapeutics of Tq and its analogs to treat kidney cancer. However, a detailed investigation on in vivo models is recommended.

Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

BACKGROUND: The change in renal function induced by first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma remains unclear. METHODS: One hundred and thirty-four patients were evaluated. Sunitinib (SU) and sorafenib (SO) were administered to 91 (67.9%) and 43 (32.1%) patients, respectively. The change in estimated glomerular filtration rate (ΔeGFR) was calculated as [(eGFR at each time point - pre-treatment eGFR)/pre-treatment eGFR] × 100. ΔeGFR was compared between SU- and SO users using a mixed-effects model for repeated measures data with two or greater. Additionally, predictors for ΔeGFR ≤ -10% at 6 months after therapy initiation were evaluated using multivariate logistic regression analysis. RESULTS: Throughout the 24 months after therapy initiation, ΔeGFR was negatively greater in SU users, compared with that in SO users (P < 0.0001). In SU users, renal dysfunction was observed regardless of pre-treatment chronic kidney disease (CKD) status, whereas the magnitude of renal dysfunction was milder in SO users. In SO users without pre-treatment CKD, renal function did not significantly deteriorate. Moreover, ΔeGFR ≤ -10% was more frequently observed in SU users after 3 months (P = 0.0121) and 6 months (P = 0.0009). Finally, SU usage was an independent predictor for ΔeGFR ≤ -10% at 6 months (odds ratio 8.87, P = 0.0053), along with pre-treatment hypertension (odds ratio 4.69, P = 00072). CONCLUSIONS: Deterioration of renal function was stronger with SU than SO. During SU therapy, renal function should be monitored and pre-treatment kidney function should be taken into consideration for therapy selection.

Safety and Efficacy of Thermal Ablation for Small Renal Masses in Solitary Kidney: Evidence from Meta-Analysis of Comparative Studies.

OBJECTIVE: To evaluate comparative renal functional preservation, perioperative and oncologic outcomes, and complications of thermal ablation (TA) versus partial nephrectomy (PN) in management of Small renal masses (SRMs) in solitary kidney. METHODS AND FINDINGS: Medline, Embase, Web of Science and the Cochrane Library were systematically searched. A meta-analysis for comparative studies comparing TA with PN was performed. According to predefined inclusion criteria, seven datasets were identified from 8 observational studies including a total of 628 patients. Cumulated data showed the changes of creatinine (p=0.02) and estimated glomerular filtration rate (eGFR) (p<0.0001) in TA arm were significantly less than these in PN arm. Significantly less new-set chronic kidney disease (CKD) was observed in TA group (p=0.04). In terms of postoperative dialysis rate, the difference favoring TA was also noted, though there is no statistical significance (p=0.09). With regard to perioperative outcomes, our data demonstrated that patients who underwent TA had significantly shorter operation time (p=0.002), less blood loss (p<0.0001), shorter length of stay (p<0.00001), and less transfusion rate (p=0.01) than those underwent PN. In addition, patients underwent TA suffered less intra- and postoperative complications (p=0.007, p<0.00001; respectively). With regard to oncologic outcomes, disease-free survival (DFS) (p<0.00001) and cancer-specific survival (CSS) (p=0.01) in the PN arm were significantly better than these of the TA arm. But, TA yielded a comparable overall survival to PN (p=0.40). Sensitivity analyses led to very similar results with overall results, and confirmed its stability. CONCLUSIONS: Our analysis indicates that PN have advantage in controlling cancer recurrence. However, TA is associated with significantly better renal functional preservation and perioperative outcomes, and less complications without increasing overall death. Our data suggest that indication for TA may be extended to select younger, healthier patients who desire a much less invasive therapeutic option.

Genotype Correlations With Blood Pressure and Efficacy From a Randomized Phase III Trial of Second-Line Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma.

BACKGROUND: In the phase III axitinib second-line (AXIS) trial, axitinib significantly prolonged progression-free survival (PFS) versus sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Analyses of associations between germline single-nucleotide polymorphisms (SNPs) and outcomes are reported. PATIENTS AND METHODS: DNA samples from blood were genotyped using TaqMan allelic discrimination. Logistic/Cox regression analyses were used to evaluate association of 15 SNPs in vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, or hypoxia-inducible factor (HIF)-1α with outcomes for blood pressure (BP; Grade ≥ 3 hypertension, diastolic BP > 90 mm Hg, and increase ≥ 15 mm Hg from baseline) and efficacy (independent review committee-assessed objective response rate and PFS, and overall survival [OS]). Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS and OS. RESULTS: Genotype data were available for 305 (42.7%) of 714 patients; 159 received axitinib and 146 sorafenib. After Bonferroni adjustment, no SNP was associated with BP outcomes. In axitinib-treated patients, VEGF-A rs699947 (A/A vs. C/C) and rs833061 (C/C vs. T/T) were associated with longer OS (27.0 vs. 13.4 months; hazard ratio [HR], 0.39; Padjusted = .015). In sorafenib-treated patients, VEGFR2 rs2071559 (G/G vs. A/A) was associated with longer OS (26.8 vs. 13.8 months; HR, 0.41; Padjusted = .030). In multivariate analyses, no SNP predicted axitinib efficacy; VEGFR2 rs2071559 predicted PFS (P = .0053) and OS (P = .0027) for sorafenib. Sensitivity/specificity of VEGFR2 rs2071559 for OS was < 80%. CONCLUSION: No SNP predicted axitinib outcomes. Although VEGFR2 rs2071559 predicted sorafenib efficacy in patients with mRCC, sensitivity/specificity limitations preclude its use for selecting individual patients for sorafenib treatment.

Impairment of cognitive functioning during Sunitinib or Sorafenib treatment in cancer patients: a cross sectional study.

BACKGROUND: Impairment of cognitive functioning has been reported in several studies in patients treated with chemotherapy. So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning. We investigated the objective and subjective cognitive function of patients during treatment with VEGFR tyrosine kinase inhibitors (VEGFR TKI). METHODS: Three groups of participants, matched on age, sex and education, were enrolled; 1. metastatic renal cell cancer (mRCC) or GIST patients treated with sunitinib or sorafenib (VEGFR TKI patients n = 30); 2. patients with mRCC not receiving systemic treatment (patient controls n = 20); 3. healthy controls (n = 30). Sixteen neuropsychological tests examining the main cognitive domains (intelligence, memory, attention and concentration, executive functions and abstract reasoning) were administered by a neuropsychologist. Four questionnaires were used to assess subjective cognitive complaints, mood, fatigue and psychological wellbeing. RESULTS: No significant differences in mean age, sex distribution, education level or IQ were found between the three groups. Both patient groups performed significantly worse on the cognitive domains Learning & Memory and Executive Functions (Response Generation and Problem Solving) compared to healthy controls. However only the VEGFR TKI patients showed impairments on the Executive subdomain Response Generation. Effect sizes of cognitive dysfunction in patients using VEGFR TKI were larger on the domains Learning & Memory and Executive Functions, compared to patient controls. Both patients groups performed on the domain Attention & Concentration the same as the healthy controls. Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks. CONCLUSIONS: Our data suggest that treatment with VEGFR TKI has a negative impact on cognitive functioning, specifically on Learning & Memory, and Executive Functioning. We propose that patients who are treated with VEGFR TKI are monitored and informed for possible signs or symptoms associated with cognitive impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01246843.

Thermal ablation in renal cell carcinoma: what affects renal function?

Because of its minimally invasive nature, thermal ablation is increasingly performed in patients with renal cell carcinoma (RCC) who are poor surgical candidates. Thermal ablation has been associated with excellent outcomes, and thus has been regarded as a viable alternative to nephron-sparing surgery. Many papers report minimal to no reduction in renal function after ablation therapies. However, in order to achieve good local control, normal renal tissue must be sacrificed, subsequently leading to reduced renal function. The amount of normal renal tissue to be ablated depends on the size, location, and number of RCCs, as well as the type of thermal ablation applied. However, there are few reports about what reduces renal function following thermal ablation therapies. The purpose of this review was to discuss factors that affect reduction in renal function and to assess the relationship between local tumour control and renal function.

Safety and treatment patterns of multikinase inhibitors in patients with metastatic renal cell carcinoma at a tertiary oncology center in Italy.

BACKGROUND: Multikinase inhibitors (MKIs) sunitinib and sorafenib have become a standard of care for metastatic renal cell carcinoma (mRCC). This study assessed safety and treatment patterns for these agents in a real-world clinical practice setting in Italy. METHODS: A retrospective medical record review was performed at a tertiary oncology center in Italy. The study included MKI-naïve non-trial patients ≥18 years old, with a histological diagnosis of mRCC, and who received sunitinib or sorafenib as first MKI during 9/2005-7/2008. Data were collected on adverse events (AEs), treatment modifications (discontinuations, interruptions, dose changes), and reasons for these modifications. RESULTS: 145 patients were included; 85 received sunitinib and 60 received sorafenib as first-line MKI. Median treatment duration was 6.6 (sunitinib) and 5.8 (sorafenib) months. 97.6% and 70.0% of patients receiving sunitinib and sorafenib, respectively, experienced ≥1 AE; 27.1% and 31.7% had ≥1 grade 3/4 AE. The most common any grade AE for sunitinib was fatigue/asthenia (81.2%), followed by mucositis/stomatitis (58.8%) and decreased taste sensation (42.4%), while for sorafenib this was fatigue/asthenia (43.3%) followed by hand-foot syndrome (38.3%) and diarrhea (31.7%). Treatment discontinuation, interruption, and dose reduction due to AEs occurred in 11.8%, 23.5%, and 30.6%, respectively, of patients receiving sunitinib, and 5.0%, 23.3%, and 36.7%, respectively, of patients receiving sorafenib. CONCLUSIONS: In this retrospective study, most patients experienced ≥1 AE during first-line MKI treatment. AEs were reported frequently and resulted in treatment modifications in 40% of patients receiving sunitinib and 45% of patients receiving sorafenib. These results suggest a need for additional effective and more tolerable treatments for mRCC.

Novel management of pruritus in patients treated with IL-2 for metastatic renal cell carcinoma and malignant melanoma.

Pruritus has been a side effect, associated with several biologic response modifiers, most commonly interferons and interleukins. Reports of pruritus are anecdotal and have not been a focus of attention. Itch fibers are essentially pain fibers, and gabapentin is used for neuropathic pain. This has led to our formal investigation of gabapentin for interleukin-2 (IL-2)-related pruritus. Clinical records of 54 patients treated with high-dose IL-2 from January 2005 to December 2006 were reviewed. Among 30 patients, who complained of pruritus, 17 patients were given gabapentin. These 17 patients were interviewed using a specific IRB approved questionnaire, which quantified pruritus according to CTCAE v3.0 criteria. According to CTCAE scale, the mean pruritus before gabapentin was 2.41, which decreased to 0.65 after gabapentin treatment and was statistically significant (P<0.0005). IL-2 therapy is frequently associated with varying degrees of peripheral eosinophilia. Relationship between pruritus and the degree of eosinophilia was also analyzed. Patients grouped into mild eosinophilia (eosinophil count<1500/mL) and moderate to severe eosinophilia (eosinophil count>1500/mL) during HDIL-2 therapy was evaluated for pruritus. χ² test for independence of variable between degree of eosinophilia and pruritus was 0.714 with no statistically significant correlation. To summarize, gabapentin is used in our facility with excellent response against pruritus. Hypothesizing the likely mechanism of pruritus in patients treated with IL-2, we suggest that gabapentin should be considered an effective and safe treatment in IL-2-related pruritus, and this concept could be applied to pruritus encountered in similar clinical settings.

First report on Cydonia oblonga Miller anticancer potential: differential antiproliferative effect against human kidney and colon cancer cells.

The present study reports the phenolic profile and antiproliferative properties of quince (Cydonia oblonga Miller) leaf and fruit (pulp, peel, and seed) against human kidney and colon cancer cells. The phenolic profiles of quince methanolic extracts were determined by high-performance liquid chromatography (HPLC)/diode array detector (DAD). 5-O-Caffeoylquinic acid was always one of the two major phenolic compounds present in all extracts, except for seed. Our results revealed that quince leaf and fruit extracts exhibited distinctive antiproliferative activities. The extracts from quince leaf showed concentration-dependent growth inhibitory activity toward human colon cancer cells (IC(50) = 239.7 +/- 43.2 microg/mL), while no effect was observed in renal adenocarcinoma cells. Concerning the fruit, seed extracts exhibited no effect on colon cancer cell growth, whereas strong antiproliferative efficiency against renal cancer cells was observed for the highest concentration assayed (500 microg/mL). The antiproliferative activity of pulp and peel extracts was low or absent in the selected range of extract concentrations. This is the first report showing that C. oblonga may be useful as a cancer chemopreventive and/or chemotherapeutic agent.

Indicadores pronósticos anatomopatológicos del cáncer de riñón / Pathological prognostic indicators in renal cell carcinoma

Objetivo: analizar el valor pronóstico independiente de supervivencia de factores anatomopatológicos no valorados de modo rutinario, como necrosis tumoral, invasión microvascular e invasión del seno renal. Material y métodos: se realizó un estudio retrospectivo y analítico incluyendo las piezas de 139 cánceres renales, intervenidos entre enero de 1993 y diciembre de 2005, clínicamente localizados. Las variables analizadas fueron: necrosis tumoral, invasión microvascular e invasión del seno renal. Se compararon con los factores clásicos: clasificación TNM, gradación de Fuhrman y tamaño tumoral. Para el análisis estadístico las variables analizadas fueron categorizadas en: pT1,2 frente a pT3,4, Fuhrman 1,2 frente a 3,4, diámetro tumoral < 7 cm frente a diámetro tumoral ≥ 7, necrosis tumoral frente a no necrosis tumoral, invasión microvascular frente a no invasión microvascular e invasión del seno renal frente a no invasión del seno renal. Se calculó la probabilidad de supervivencia cáncer específica y el periodo libre de enfermedad. Se realizó el análisis estadístico descriptivo y analítico con el empleo de regresión logística para análisis univariante y multivariante. El periodo libre de enfermedad se estimó mediante el modelo de regresión de Cox y curvas de Kaplan-Meier. Resultados: en el análisis univariante todas las variables analizadas influyen de forma significativa en la muerte por cáncer de riñón. En el análisis multivariante la variable que más influye es el grado de Fuhrman (p = 0,032). En el periodo libre de enfermedad estimado por el método de Cox las variables que influyen de forma significativa son la categoría pT (p = 0,038) y el grado de Fuhrman (p = 0,048). Conclusión: en pacientes con cáncer renal clínicamente localizado la categoría pT y el grado de Fuhrman son los factores pronósticos anatomopatológicos más importantes en cuanto a la supervivencia y el periodo libre de enfermedad. La invasión microvascular, la necrosis tumoral y la invasión tumoral del seno renal son factores pronósticos de muerte por cáncer renal que se asocian con la categoría TNM, el grado de Fuhrman y tamaño tumoral(AU)

Objective: To analyze histological factors not routinely assessed as potential prognostic factors in renal cell carcinoma, such as tumor necrosis, microscopic vascular invasion, and sinus fat invasion. Materials and methods: a retrospective, analytical study was conducted of surgical specimens from 139 patients with localized renal cell carcinoma who underwent nephrectomy from 1993 to 2005. Tumor necrosis, microscopic vascular invasion, and sinus fat invasion were analyzed and compared to the classical factors: TNM classification, Fuhrman grade, and tumor size. For statistical analysis, variables analyzed were categorized as pT1, 2 vs pT3, 4; Fuhrman grade 1, 2 vs 3, 4; tumor size < 7 cm vs ≥ 7cm; tumor necrosis vs no tumor necrosis; microvascular invasion of sinus fat vs no invasion. Cancer-specific survival probability and disease-free survival were calculated. A descriptive and analytical statistical analysis was performed using logistic regression for univariate and multivariate analyses. Dependent variables were used to analyze cancer-specific survival rates. Disease-free survival was estimated using a Cox regression model and Kaplan-Meier curves. Results: In the univariate analysis, all variables analyzed had a significant influence on death for renal cell carcinoma. In the multivariate analysis, the variable having the greatest influence was Fuhrman grade (p = 0,032). The variables significantly influencing disease-free survival, estimated by the Cox method, were the pT stage (p = 0.038) and Fuhrman grade (p = 0.048). Conclusions: In patients with clinically localized renal cell carcinoma undergoing nephrectomy, pT stage and Fuhrman grade are the most important prognostic factors for survival and disease-free survival. Tumor necrosis, microscopic vascular invasion, and sinus fat invasion are prognostic factors for death from renal carcinoma which are associated to TNM classification, Fuhrman grade, and tumor size(AU)

Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer.

Metastatic renal cell carcinoma (mRCC) is a highly vascularized tumor with a generally poor prognosis. It is largely resistant to conventional cancer treatment, including most schemes of hormonal and cytokine therapy as well as to modern chemotherapy. Although IFN-alpha has been the first choice in mRCC treatment strategies for more than a decade, recent recommendations of the European Association of Urology focus on so-called molecular-targeted therapies, with multikinase inhibitors, such as sorafenib and sunitinib, blocking the progression of cell proliferation and tumor angiogenesis, as preferential therapy. Sorafenib targets the VEGF receptor, the PDGF receptor beta and, finally, Raf kinase, and is approved for patients who have either received cytokines or are unsuitable for such a therapy. Although targeted therapies reveal superior efficacy compared with previous cytokine-based approaches, they do not cure patients with metastatic disease. Therefore, following tumor progression, most patients require a second-line or sequential therapy during the further progress of the disease. Owing to the fact that optimal sequencing of these new agents has not been fully elucidated, some recent mainly retrospective studies compared the sequence of sorafenib and sunitinib in order to assess the best clinical benefit in mRCC patients. Apparently, no cross-resistance could be observed in any trial, and most results demonstrated a superior efficacy of a sequence strategy when sorafenib was applied as first-line treatment. Regarding current investigations, the aim of the present article is to address and critically discuss the clinical data concerning the efficacy of sorafenib as part of a sequential treatment of mRCC.

Safety and efficacy of sorafenib therapy in patients with metastatic kidney cancer with impaired renal function.

PURPOSE: Sorafenib is an oral Raf kinase inhibitor, approved for the treatment of advanced renal cancer. Clinical investigation of the safety and feasibility of sorafenib therapy in patients with impaired renal function was performed in this study. MATERIALS AND METHODS: The protocol was approved by the Human Investigation Committee of Wayne State University. Medical records of patients with metastatic renal cancer at Wayne State University started on sorafenib between November 2005 to January 2007 were reviewed. Patients with a calculated creatinine clearance (CrCl) of 60 mL/min or less (chronic kidney disease stage 3 or greater per Kidney Disease Outcomes Quality Initiative guidelines) were deemed to have renal insufficiency. RESULTS: A total of 32 patients who met the selection criteria were analyzed. Fourteen of 32 (44%) patients had renal insufficiency (range, 32-60 mL/min). Median age was 71 years in patients with CrCl < or = 60 mL/min and 54 years in those with > 60 mL/min. Incidence of diarrhea (57% vs. 33%) and hand-foot syndrome (86% vs. 56%) were higher in the renal-dysfunction group. Dose interruptions and dose reductions were noted in 57% and 43% of patients with renal dysfunction versus 28% and 22% in those without. No significant differences were noted in response rate, progression-free survival or overall survival. CONCLUSION: Renal insufficiency is frequently observed in patients with advanced renal cancer. Sorafenib therapy can be safely delivered in patients with mild and moderate renal dysfunction, and efficacy appears to be maintained.

Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.

For almost the last two decades, interleukin-2 and interferon-alpha have been the only systemic treatment options available for metastatic renal cell carcinoma. However, in recent years, five new targeted therapies namely sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab have demonstrated clinical activity in these patients. With the availability of new targeted agents that are active in this disease, there is a need to continuously update the treatment algorithm of the disease. Due to the important advances obtained, the Spanish Oncology Genitourinary Group (SOGUG) has considered it would be useful to review the current status of the disease, including the genetic and molecular biology factors involved, the current predicting models for development of metastases as well as the role of surgery, radiotherapy and systemic therapies in the early- or late management of the disease. Based on this previous work, a treatment algorithm was developed.

Cryoablation and radiofrequency for kidney tumor.

The detection of incidental and asymptomatic renal cortical neoplasms has concomitantly increased with radiographic imaging use. The gold standard for treating small renal tumors includes open and laparoscopic partial nephrectomy. Ablative renal procedures intend to duplicate the excellent oncologic outcomes of partial nephrectomy, while decreasing complications and shortening hospitalization time and convalescence. Only short and medium-term data are available, but ablation with cryotherapy or radiofrequency probes may achieve these goals. Ablation also offers the advantages of a minimally invasive surgical approach, with a significantly lower complication rate than partial nephrectomy. Ablated lesions are typically left in situ. Leaving potentially malignant tissues in place, albeit in a nonviable condition, certainly represents a major change in surgical thinking processes. This article reviews the status of cryoablation and radiofrequency ablation, the two ablative modalities currently available for clinical application.

Safety and tolerability of sorafenib in clear-cell renal cell carcinoma: a Phase III overview.

This review summarizes the safety of sorafenib, an oral multikinase inhibitor, focusing on the randomized, placebo-controlled, Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) in renal cell carcinoma, which formed the basis of the approval of sorafenib. Similar to other targeted agents, sorafenib acts primarily to induce disease stabilization, rather than tumor regression, suggesting that long-term administration is necessary. The tolerability of an agent is important in long-term treatment, and a predictable and manageable side-effect profile is advantageous. Although IL-2 and interferon have been standard care treatments for advanced renal cell carcinoma for over a decade, they are poorly tolerated. Targeted agents offer an alternative for patients with advanced renal cell carcinoma, as initial therapy or after failure of cytokine treatment.

Sorafenib and sunitinib: novel targeted therapies for renal cell cancer.

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.