Kidney Cancer - Volume 3, issue 2

Authors: Nizam, Amanda | Rhea, Logan P. | Gupta, Brinda | Aragon-Ching, Jeanny B.

Article Type: Review Article

Abstract: The advent of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) a decade ago revolutionized the treatment paradigm in advanced metastatic clear cell renal cell carcinoma (RCC) with improved survival rates compared to the pre-TKI era. Monotherapy with VEGF TKIs has remained first-line. However, sequencing of different TKIs, mammalian target of rapamycin (mTOR) inhibitors, or immune checkpoint inhibitors (ICIs) has been the subject of controversy in the treatment landscape of metastatic RCC. First-line treatment further evolved with the approval of nivolumab plus ipilimumab in intermediate-and poor-risk patients based on an overall survival (OS) benefit demonstrated in the CheckMate214 trial …as well as a progression-free survival (PFS) benefit of cabozantinib in the CABOSUN trial. Optimal sequencing, patient selection, and understanding resistance pathways continue to be prominent concerns. Efforts to bypass resistance mechanisms have led to the study of combination therapies. Given enhancement of immune checkpoint inhibitor (ICI) T-cell mediated effects by VEGF-mediated immunosuppression, the combination of VEGF inhibitors and ICIs in treatment-naïve locally advanced and metastatic RCC has shown promise. Available results of phase III trials utilizing these combinations are discussed herein. Show more

Keywords: Immunotherapy, VEGF inhibitors, immune checkpoint inhibitors (ICIs), advanced renal cell cancer

DOI: 10.3233/KCA-190050

Citation: Kidney Cancer, vol. 3, no. 2, pp. 81-91, 2019

Authors: Zahoor, Haris | Duddalwar, Vinay | D’Souza, Anishka | Merseburger, Axel S. | Quinn, David I.

Article Type: Review Article

Abstract:  The treatment landscape of advanced renal cell carcinoma (RCC) is rapidly evolving. Immune checkpoint inhibitors (ICI) have now become the preferred first line treatment with the approval of nivolumab and ipilimumab combination in intermediate to poor risk patients. Combination/s of ICI with vascular endothelial growth factor (VEGF) inhibitors will also be approved in future. The optimal treatment of patients who progress on ICI-based therapies is not well defined as of yet. In this review, we discuss the data regarding various treatment options available in this space, their limitations, and also provide our opinion regarding treatment selection.

Keywords: Renal cell carcinoma, immuno-oncology, immune checkpoint inhibitor, tyrosine kinase inhibitors

DOI: 10.3233/KCA-190053

Citation: Kidney Cancer, vol. 3, no. 2, pp. 93-102, 2019

Authors: Bruchbacher, Andreas | Nachbargauer, Sebastian | Fajkovic, Harun | Schmidinger, Manuela

Article Type: Research Article

Abstract: Background and objective: Sunitinib has been a standard treatment for patients with metastatic renal cell carcinoma (mRCC) since 2006. However, almost all patients will eventually progress. Besides well described mechanisms of primary or secondary resistance, insufficient drug exposure may lead to disease progression. The aim of this study was to identify patients in whom sunitinib dose escalation was performed and to analyse safety and efficacy of this strategy in clinical practice. Methods: A single-centre retrospective study on dose escalation in mRCC patients who were treated with sunitinib at the Medical University of Vienna between January 2011 and May …2016. Dose escalation was studied in patients who had either progressed (cohort 1: PDescal ) or had stable disease with minor progression (cohort 2: SDescal ). The primary endpoints were response rate before and after dose escalation, global progression free survival and overall survival. Secondary endpoints were treatment duration before and after dose escalation and toxicity. Results: Dose escalation up to 75 mg was offered in 21 out of 265 patients. Response rates before and after dose escalation were 42,8% and 23.8%, respectively. The median global PFS and OS were 15.60 and 32.95 months, respectively. The median treatment duration before and after dose escalation was 6.1 months (1.3–29.3 months) and 6.6 months (2.5–16.6 months). No new toxicities emerged under escalated dose and no grade 4 adverse events occurred. Conclusion: Sunitinib dose escalation may be a strategy in patients with few toxicities at the time point of progression. Show more

Keywords: Metastatic renal cell carcinoma, sunitinib, dose escalation, resistance

DOI: 10.3233/KCA-190055

Citation: Kidney Cancer, vol. 3, no. 2, pp. 103-110, 2019

Authors: Synold, Timothy W. | Plets, Melissa | Tangen, Catherine M. | Heath, Elisabeth I. | Palapattu, Ganesh S. | Mack, Philip C. | Stein, Mark N. | Meng, Maxwell V. | Lara, Primo | Vogelzang, Nicholas J. | Thompson, Ian Murchie | Ryan, Christopher W.

Article Type: Research Article

Abstract: Background: S0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity. Methods: Patients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) …based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: A total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0–12.9, 12.9–22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p  < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p  = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p  = 0.02 and OR = 2.63; p  = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p  = 0.01 and OR = 2.90; p  = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p  = 0.05). Conclusions: We identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity. Show more

Keywords: Renal cell carcinoma, everolimus, pharmacokinetics, adjuvant chemotherapy, therapeutic drug monitoring

DOI: 10.3233/KCA-180049

Citation: Kidney Cancer, vol. 3, no. 2, pp. 111-118, 2019

Authors: Gong, Xue | Zhao, Hongjuan | Saar, Matthias | Peehl, Donna M. | Brooks MD, James D.

Article Type: Research Article

Abstract: Background: Clear cell renal cell carcinoma (ccRCC) is molecularly diverse and distinct molecular subtypes show different clinical outcomes. MicroRNAs (miRNAs) are essential components of gene regulatory networks and play a crucial role in progression of many cancer types including ccRCC. Objective: Identify prognostic miRNAs and determine the role of miR-22 in ccRCC. Methods: Hierarchical clustering was done in R using gene expression profiles of over 450 ccRCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was performed to identify prognostic miRNAs in the TCGA dataset. RNA-Seq was performed to identify miR-22 target genes in primary …ccRCC cells and Matrigel invasion assay was performed to assess the effects of miR-22 overexpression on cell invasion. Results: Hierarchical clustering analysis using 2,621 prognostic genes previously identified by our group demonstrated that ccRCC patients with longer overall survival expressed lower levels of genes promoting proliferation or immune responses, while better maintaining gene expression associated with cortical differentiation and cell adhesion. Targets of 26 miRNAs were significantly enriched in the 2,621 prognostic genes and these miRNAs were prognostic by themselves. MiR-22 was associated with poor overall survival in the TCGA dataset. Overexpression of miR-22 promoted invasion of primary ccRCC cells in vitro and modulated transcriptional programs implicated in cancer progression including DNA repair, cell proliferation and invasion. Conclusions: Our results suggest that ccRCCs with differential clinical outcomes have distinct transcriptomes for which miRNAs could serve as master regulators. MiR-22, as a master regulator, promotes ccRCC progression at least in part by enhancing cell invasion. Show more

Keywords: MicroRNA, clear cell renal cell carcinoma, survival, TCGA, miR-22

DOI: 10.3233/KCA-190051

Citation: Kidney Cancer, vol. 3, no. 2, pp. 119-132, 2019

Authors: Ramalingam, Sundhar | Walker, Mark | George, Daniel J. | Harrison, Michael R.

Article Type: Research Article

Abstract: Background: No studies have looked at comparative outcomes in the treatment of metastatic renal cell carcinoma (mRCC) between academic and community practice settings. Methods: We created a joint academic (ACAD) and community (COMM) retrospective registry of patients treated for mRCC. This registry represents a collaboration of an academic research network (Duke Oncology Network; Durham, NC) and a community-based oncology network (ACORN Research; Memphis, TN) of multiple member practices. We compared progression free survival and overall survival between these centers. We included patients diagnosed with mRCC after January 1, 2007 and before February 7, 2011. Results: Four …hundred and fifty-five patients were captured in the registry including N = 255 COMM patients and N = 200 ACAD patients. Initial analysis of COMM patients showed a median PFS of 6.24 months [95% CI, 5.4, 7.5], 3.88 months [95% CI, 3.0, 4.8], and 3.35 months [95% CI 2.9, 4.4] with first, second, and third line systemic therapy. ACAD patients had longer median PFS estimates of 11.3 months [95% CI, 7.5, 13.6], 4.4 months [95% CI, 2.7, 8.9], and 5.22 months [95% CI, 2.7, 6.3] respectively. Median OS was 12.06 months [95% CI 8.7, 15.4] among COMM patients and 36.73 months [95% CI 26.2 42.2) among ACAD patients. Differences persisted with inclusion of well-established prognostic models and predictive factors such as treatment exposures. Conclusions: There may be differences between outcomes for mRCC patients in community versus academic settings; however rselection most likely plays a role and we need further studies to determine reasons for these potential disparities. A prospective metastatic renal cell carcinoma (MaRCC) registry has been accrued encompassing sixty academic and community treatment sites across the United States rwith the goal of examining real-world treatment patterns and outcomes; MaRCC may shed further light on any potential outcomes differences. Show more

Keywords: Kidney neoplasms, renal cell carcinoma, outcome assessment, healthcare disparities

DOI: 10.3233/KCA-190059

Citation: Kidney Cancer, vol. 3, no. 2, pp. 133-140, 2019

Authors: Parikh, Mamta

Article Type: Other

DOI: 10.3233/KCA-199001

Citation: Kidney Cancer, vol. 3, no. 2, pp. 141-142, 2019