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Introduction: γ-Glutamyltransferase is reportedly associated with survival in local and metastatic renal cell carcinoma patients; however, its predictive role among patients treated with immune-checkpoint inhibitors are unknown. This study aimed to investigate the role of γ-glutamyltransferase as a predictive marker among metastatic renal cell carcinoma patients undergoing nivolumab therapy. Methods: We retrospectively evaluated 69 nivolumab-treated metastatic renal cell carcinoma patients upon failure of one or more systematic therapies. Serum γ-glutamyltransferase levels were determined at baseline and 2 months after nivolumab treatment initiation. Patients were classified as high (≥ 49 U/L) and low (< 49 mg/dL) from baseline GGT levels and the outcomes were compared between the two groups. Furthermore, increased (after/baseline ≥ 2) and non-increased (after/baseline < 2) groups were compared. Progression-free survival and overall survival were evaluated after nivolumab initiation. Results: Overall survival was significantly shorter in the high baseline γ-glutamyltransferase group (20.3%) than in the low group (79.7%) (median 2.33 vs not reached [months], p = 0.0051). Progression-free survival and the overall survival were significantly shorter in the increased than in the non-increased group (24.6% and 75.4%, respectively) (median PFS: 4.43 vs 7.23 [months], p = 0.0373/OS: 24.00 vs not reached, p = 0.0467). On multivariate analyses, high baseline γ-glutamyltransferase was an independent factor for overall survival (p = 0.0345) and increased γ-glutamyltransferase was an independent factor for progression-free survival (p = 0.0276) and overall survival (p = 0.0160). Conclusions: High baseline γ-glutamyltransferase and its early increase are associated with a poor prognosis in metastatic renal cell carcinoma patients receiving nivolumab. Serum γ-glutamyltransferase levels may help predict treatment outcomes. [ABSTRACT FROM AUTHOR]

Cytoreductive nephrectomy (CN) followed by systemic therapy had been considered the standard of care for metastatic renal cell carcinoma (mRCC) patients since two clinical trials established its role during the cytokines era. With introduction of new and effective drugs, such as vascular endothelial growth factor-targeted therapies, the role of CN started to be challenged. Retrospective studies conducted during the targeted therapy era pointed to better outcomes when CN was associated with systemic treatment, although certain patients with poor risk features did not seem to benefit. Therefore, prospective clinical trials supporting CN were needed. Recently, with the publication of two randomized trials evaluating CN in the targeted therapy era, it has been made clear that patient selection and multidisciplinary discussion are of paramount importance in order to achieve the best outcomes. We reviewed the available literature on the role of CN among mRCC patients, commenting on how to apply the new evidence into clinical practice and providing future perspectives. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used. Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti–PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI. • Immunotherapy (ICI) is moving to front-line treatment in metastatic RCC for intermediate- and poor-risk patients. • Little data exists on responses to second-line (2L) TKI after front-line (1L) ICI. • Our data showed that 2L VEGFR-TKI have ORR 41% and DCR 94% after 1L ICI–containing regimen. • Median PFS on 2L VEGFR-TKI after 1L ICI in metastatic clear-cell RCC was 13.2 mo. • Safety and tolerability of 2L VEGFR-TKI after 1L ICI is typical of class effects. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the functional and oncologic outcomes of minimally invasive cytoreductive nephrectomy (CN) in three high-volume cancer centers. Patients and methods: Three prospectively maintained, IRB-approved kidney surgery databases were queried from three high-volume cancer centers. All patients who underwent minimally invasive surgery (laparoscopic, hand-assisted laparoscopic, or robotic) partial or radical CN with existing measurable extra-renal metastatic disease between May 2001 and May of 2013 were included in this analysis. Results: We identified 120 patients who underwent minimally invasive CN for metastatic renal cell carcinoma. Most of the surgeries were radical (93.3 %) and performed laparoscopically (96.6 %). Median operative time was 210 min, with a median estimated blood loss of 150 cc, and 11 (9.2 %) patients received blood transfusions. Four (3.3 %) patients were converted to open surgery due to locally advanced disease and/or bleeding. Postoperative complications were seen in 28 (23.3 %) patients, of which 20 (71.4 %) were classified as minor (Clavien-Dindo I-II). The median survival of the entire cohort was 25.7 months, with a 3-year survival rate of 35 %. Multivariate analysis indicated that only hypertension, brain metastasis, and pT stage were independently associated with worse overall survival (HR > 1). Conclusions: Minimally invasive cytoreductive nephrectomy is feasible and safe in experienced hands with acceptable morbidity and oncological outcomes. [ABSTRACT FROM AUTHOR]

Purpose: In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16-20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. Materials and methods: All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. Results: 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48-1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39-1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09-0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23-0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable. Conclusions: Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses. [ABSTRACT FROM AUTHOR]

Between December 2005 and October 2009, FDA approved six targeted therapies shown to significantly extend survival for advanced renal cell carcinoma ( RCC) patients in clinical trials. This study aimed to examine changes in survival between the pretargeted and targeted therapy periods in advanced RCC patients in a real-world setting. Utilizing the 2000-2010 SEER Research files, a pre-post study design with a contemporaneous comparison group was employed to examine differences in survival outcomes for patients diagnosed with advanced RCC (study group) or advanced prostate cancer (comparison group, for whom no significant treatment innovations happened during this period) across the pretargeted therapy era (2000-2005) and the targeted therapy era (2006-2010). RCC patients diagnosed in the targeted therapy era ( N = 6439) showed improved survival compared to those diagnosed in the pretargeted therapy era ( N = 7231, hazard ratio ( HR) for all-cause death: 0.86, P < 0.01), while the change between the pre-post periods was not significant for advanced prostate cancer patients ( HR: 0.97, P = 0.08). Advanced RCC patients had significantly larger improvements in overall survival compared to advanced prostate cancer patients ( z = 4.31; P < 0.01). More detailed year-to-year analysis revealed greater survival improvements for RCC in the later years of the posttargeted period. Similar results were seen for cause-specific survival. Subgroup analyses by nephrectomy status, age, and gender showed consistent findings. Patients diagnosed with advanced RCC during the targeted therapy era had better survival outcomes than those diagnosed during the pretargeted therapy era. Future studies should examine the real-world survival improvements directly associated with targeted therapies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Despite level 1 evidence demonstrating a survival benefit of cytoreductive nephrectomy (CN) in well-selected patients with metastatic renal cell carcinoma (mRCC) in the cytokine era, its role in the contemporary period of targeted therapy remains understudied. To help facilitate improved patient selection for CN and clinical trial design in the targeted therapy era, this study sought to identify factors associated with RCC-specific survival in patients diagnosed with mRCC and undergoing CN between 2005 and 2010 using a large population-based cohort. Materials and methods: Patients diagnosed with mRCC and undergoing CN between 2005 and 2010 were identified from the Surveillance Epidemiology and End Results cancer database. Kaplan-Meier methods were used to calculate disease-specific survival. Stepwise multivariable Cox proportional hazards regression analysis was used to identify factors independently associated with risk of RCC-specific death. Results: A total of 2,478 patients were identified who were eligible for analysis with a median disease-specific survival of 21 months (95% CI: 19, 22). Factors independently associated with an increased risk of RCC-specific death included age at diagnosis≥60 years, African American race, higher American Joint Committee on Cancer T stage (≥T3), high Fuhrman nuclear grade (3 or 4), primary tumor size≥7cm, regional lymphadenopathy, both distant lymph node and visceral metastases, and sarcomatoid histology. A higher number of adverse factors correlated with an increased risk of RCC-specific death (P<0.001). Conclusions: Factors associated with RCC-specific survival identified in this large population-based study can be used to better stratify patients suitable for CN and to help with future clinical trial design and interpretation. [Copyright &y& Elsevier]

Abstract: Objective: We evaluate presentation and outcome of patients with metastatic RCC to the gallbladder from our institution and published literature. Methods: Patients with a history of gallbladder metastasis from RCC were selected from our institution''s prospective database. A systematic PubMed search was performed to identify articles describing patients with metastatic RCC to the gallbladder. The final cohort included 33 patients: 4 from our institution and 29 from 28 previously published cases. Survival analysis was conducted using log-rank Kaplan-Meier analysis. Results: Median patient age was 63 years and the majority of patients were male. Most patients were asymptomatic and diagnosed with gallbladder metastasis on imaging performed for surveillance or staging. The median time to gallbladder metastasis following nephrectomy was 4 years. Metastasis to the gallbladder occurred both synchronously (33%) and metachronously (67%). Of the patients with available histology, all had clear cell RCC (n = 28). Of all patients, 13 (39%) had metastasis only to the gallbladder, while 20 (61%) had additional sites of metastasis. The most common sites of additional metastasis were contralateral kidney (30%), pancreas (21%), lung (18%), adrenal (18%), and lymph nodes (9%). All patients underwent cholecystectomy. At a median follow up time of 1.5 years after cholecystectomy, 54% of patients had no evidence of disease, 14% were alive with metastasis, 23% had died from metastatic RCC, and 9% died from causes unrelated to their cancer. Conclusion: Gallbladder metastasis from RCC is a rare event that may occur synchronously or metachronously with most patients being asymptomatic. Clear cell carcinoma appears to be the primary pathology associated with gallbladder metastasis. High rates of bilateral RCC and pancreatic metastasis suggest novel associations in patients with RCC and gallbladder metastasis. [Copyright &y& Elsevier]

Background: Recent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent. Patients and methods: The medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with preexisting cardiac risk factors were specifically scrutinized for increased expression of cardiac changes. Results: Grade 3 hypertension was seen in 17 patients (9.7%); in 12 of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left ventricular systolic (LVEF)dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). Significant univariate associations for predictors of CHF were history of hypertension (P = 0.008), history of coronary heart disease (P = 0.0005) and prior treatment with an angiotensin-converting enzyme inhibitor (P = 0.04). Multivariate analysis suggested that a history of coronary artery disease [odds ratio (OR) 18, 95% confidence interval (CI) 4-160, P = 0.005] and hypertension (OR 3, 95% CI 1.5-80, P = 0.04) was the only significant independent predictors of CHF. Conclusions: Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment. [ABSTRACT FROM PUBLISHER]