Articles

Trends in Initial Systemic Therapy for Elderly Patients with Metastatic Clear Cell Renal Cell Carcinoma

Osterman, Chelsea K. et al.
Kidney Cancer, vol. 4, no. 3, pp. 131-137, 2020
DOI: 10.3233/KCA-200089

Abstract

Background

The treatment landscape for metastatic clear cell renal cell carcinoma (mRCC) is rapidly changing. It is unknown how adoption of new types of therapies may differ by patient age.

Objective

To compare trends in first-line therapy use for older (≥70 years) and younger (< 70) patients with mRCC before and after approval of nivolumab in 2015.

Methods

Using the National Cancer Database, we assessed trends in first-line therapy use by calculating the proportion of patients receiving targeted therapy, immunotherapy, or no systemic therapy by year of diagnosis. Initial systemic treatment was compared for patients diagnosed in 2016 with patients diagnosed in 2011 as a control group prior to nivolumab approval. Multivariable regression analysis was used to evaluate the interaction between year of diagnosis and elderly status for use of first-line immunotherapy or targeted therapy.

Results

From 2006 to 2016, the proportion of patients receiving any type of systemic therapy increased from 43.7% to 56.5%. On stratified multivariable regression analysis, older patients diagnosed in 2016 were 17.3 times more likely to receive first-line immunotherapy compared to those diagnosed in 2011, while younger patients were 2.3 times more likely. There was no change in targeted therapy use over this time regardless of patient age.

Conclusions

The rate of adoption of first-line immunotherapy was particularly pronounced for elderly compared to younger patients. While first-line use of immunotherapy may have allowed elderly patients to receive systemic therapy that they otherwise would not, the efficacy of these drugs in elderly patients deserves further study.

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Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma

Dizman N, Hsu JA, Bergerot PG, et al.
Cancer Med. 2020 Nov 1.
DOI: 10.1002/cam4.3569.

Abstract

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium-containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs). mRCC patients initiating VEGF-TKIs, regardless of the line of therapy, were randomized to probiotic-supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic-restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole-metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic-supplemented arm versus two patients in the probiotic-restricted arm. Clinical benefit rate was similar in probiotic-supplemented versus probiotic-restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10-6 and p = 5.6 × 10-3 , respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617.

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Predictive Biomarkers of Response to Immunotherapy in Metastatic Renal Cell Cancer

Raimondi A, Sepe P, Zattarin E, et al.
Front Oncol. 2020 Aug 12;10:1644.
DOI: 10.3389/fonc.2020.01644.

Abstract

Introduction

In the last decades, the therapeutic decision-making approach to metastatic renal cell cancer (mRCC) has dramatically changed thanks to the introduction in the treatment scenario of, first, anti-angiogenic agents and, afterward, immune-checkpoint inhibitors (ICIs). Immunotherapy is now the standard of care in pretreated mRCC patients and has recently entered even the first line setting. Nevertheless, in mRCC as well as in other tumor settings, a durable and clinically meaningful benefit from treatment with ICIs is not obtained for all patients treated. Therefore, the necessity to identify and validate predictive biomarkers of response to immunotherapy has emerged, in order to design the optimal treatment strategy for mRCC patients.

Discussion

In this review, we present and discuss the most promising predictive biomarkers of response to ICIs in mRCC with the recent data available. In details, the first marker that was investigated is the immunohistochemical expression of programmed death receptor ligand 1 (PD-L1), showing a negative prognostic role in mRCC, but the debate about its potential predictive value is still open. Additionally, the high heterogeneity in PD-L1 determination methods adds complexity to this issue. Second, the tumor mutational or neoantigen burden is an emerging biomarker of increased response to immunotherapy, hypothesizing that the higher the TMB, the higher is the production of neoantigens, and thus the stimulation of anti-tumor immune response, even though controversial results have been obtained. Third, the tumor microenvironment, namely the different populations of the immune infiltrate, plays a key role in tumor progression and in the response to immunotherapy. Finally, several studies have collected evidence on the potential association of the occurrence of immune-related adverse events (irAEs) with the benefit from ICIs, first in non-small cell lung cancer (NSCLC) and melanoma, and recently even in mRCC.

Conclusions

Several promising biomarkers of response to immunotherapy with ICIs have been identified, though without conclusive results upon their potential predictive value in mRCC. Therefore, the results of the exploratory analyses of the recently presented first-line trials and hopefully of future prospective, biomarker-driven studies could provide useful tools to be applied in the everyday clinical practice.

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Gender Differences in the Clinical Management of clinical T1a Renal Cell Carcinoma

Metcalf MR, Cheaib JG, Wainger J, et al.
Urology. 2020 Sep 2;S0090-4295(20)31044-X.
DOI: 10.1016/j.urology.2020.08.041.

Abstract

Objective

To evaluate gender differences in the management of clinical T1a (cT1a) renal cell carcinoma (RCC) before and after release of the AUA guidelines for management in 2009, which prioritized nephron-sparing approaches.

Methods

Patients aged ≥66 years diagnosed with cT1a RCC from 2004 to 2013 in Surveillance, Epidemiology, and End Results-Medicare were analyzed. Multivariable mixed-effects logistic regression models were used to evaluate factors associated with radical nephrectomy (RN) for cT1a RCC before (2004 to 2009) and after (2010 to 2013) guidelines release. Predictors of pathologic T3 upstaging and high grade pathology in the postguidelines period were examined using multivariable logistic regression among patients who underwent RN or partial nephrectomy.

Results

Twelve thousand four hundred and two patients with cT1a RCC were identified, 42% of whom were women. Overall, the likelihood of RN decreased postguidelines (odds ratio [OR] = 0.44, P <.001), but women were at increased odds of undergoing RN both before and after guideline release (OR = 1.27, P <.001 and OR = 1.37, P <.001, respectively) upon multivariable mixed-effects logistic regression. Tumor size >2 cm was also associated with increased likelihood of RN before and after guidelines (OR = 2.61, P <.001 and OR = 2.51, P <.001, respectively). In the postguidelines period, women had significantly lower odds of pathologic upstaging (OR = 0.75, P = .024) and harboring high grade pathology (OR = 0.71, P <.001) compared to men.

Conclusions

Gender differences persist in the management of cT1a RCC, with women having higher odds of undergoing RN, even after release of AUA guidelines and despite having lower odds of pathologic upstaging and high-grade disease.

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Outcomes of complete metastasectomy in metastatic renal cell carcinoma patients: The Canadian Kidney Cancer information system experience

Dragomir A, Nazha S, Wood LA, et al.
Urol Oncol. 2020 Oct;38(10):799.e1-799.e10.
DOI: 10.1016/j.urolonc.2020.07.021.

Abstract

Background

Surgical resection of metastasis can be integrated in the management of metastatic renal cell carcinoma (mRCC) as it can contribute to delay disease progression and improve survival.

Objective

This study assessed the impact of complete metastasectomy in mRCC patients using real-world pan-Canadian data.

Design, setting and participants

The Canadian Kidney Cancer information system (CKCis) database was used to select patients who were diagnosed with mRCC between January 2011 and April 2019. To minimize selection bias, each patient having received a complete metastasectomy was matched with up to 4 patients not treated with metastasectomy.

Outcome measurements and statistical analysis

Overall survival (OS) was calculated from the date of metastasectomy or selection, to death from any cause. A Cox proportional hazards model was used to assess the impact of the metastasectomy while adjusting for potential confounding variables.

Results

A total of 229 patients undergoing complete metastasectomy were matched with 803 patients not treated with metastasectomy. After matching, baseline characteristics were well balanced between groups. After 12 months, the proportion of patients that were still alive was 96.0% and 89.8% in the complete metastasectomy and its matched group, respectively; the 5-year OS were 63.2% and 51.4%, respectively. Multivariate analysis performed in the matched cohort revealed that patients who underwent complete metastasectomy had a lower risk of mortality compared to patients who did not undergo metastasectomy (hazard ratio: 0.41, 95% confidence interval:0.27-0.63).

Conclusions

Our study found that patients who underwent complete metastasectomy have a longer overall survival and a longer time to initiation of targeted therapy compared to patients not receiving metastasectomy. These findings should support aggressive resection of metastasis in selected patients.

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Fear of Cancer Recurrence in Patients With Localized Renal Cell Carcinoma

Bergerot CD, Battle D, Philip EJ, et al.
JCO Oncol Pract. 2020 Nov;16(11):e1264-e1271.
DOI: 10.1200/OP.20.00105.

Abstract

Purpose

Patients with cancer commonly report distress and fear of cancer recurrence (FCR) impacting quality of life and clinical outcomes. This study aims to test the association between emotional well-being and clinical characteristics of survivors with localized renal cell carcinoma (RCC).

Materials and methods

Survivors with localized RCC were invited to participate in this study through social media by the Kidney Cancer Research Alliance. Participants self-reported clinical characteristics, distress (Distress Thermometer), and FCR (Fear of Cancer Recurrence-7). Ordinal regression was used to test the association between emotional well-being and patient characteristics.

Results

A total of 412 survivors were included in this analysis. Participants were mostly female (79.4%) and well educated (58.3%), with a median age of 54 years (range, 30-80 years) and median time since diagnosis of 17.5 months. More than one half were diagnosed with stage I disease (56.1%). Most patients (62.3%) had a clear understanding of their diagnosis. A high prevalence of moderate to severe distress (67.0%) and FCR (54.9%) was reported across all survivors of RCC. Higher FCR was associated with female gender, younger age, and lack of understanding of their diagnosis (P = .001), whereas more recent diagnosis was associated with higher distress levels (P = .01).

Conclusions

Our findings suggest that FCR is a common problem that is persistent after therapy and that certain individuals, including female and younger patients, may be at particular risk of experiencing clinically relevant FCR.

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Development and Validation of a Clinical Prognostic Model Based on Immune-Related Genes Expressed in Clear Cell Renal Cell Carcinoma

Ren S, Wang W, Shen H, et al.
Front Oncol. 2020 Aug 28;10:1496.
DOI: 10.3389/fonc.2020.01496

Abstract

Background

Clear cell renal cell carcinoma (ccRCC) is the most frequent and terminal subtype of RCC. Reliable markers associated with the immune response are not available to predict the prognosis of patients with ccRCC. We exploited the extensive number of ccRCC samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository to perform a comprehensive analysis of immune-related genes (IRGs).

Methods

Based on TCGA data, we incorporated IRGs and their expression profiles of 72 normal and 539 ccRCC samples. Univariate Cox analysis was used to evaluate the relationship between overall survival (OS) and IRGs expression. The Lasso Cox regression model identified prognostic genes used to establish a clinical immune prognostic model. The TF-IRG network was used to study the potential molecular mechanisms of action and properties of ccRCC-specific IRGs. Multivariate Cox analysis established a clinical prognostic model of IRGs.

Results

We found a significant correlation among 15 differentially expressed IRGs with the OS of patients with ccRCC. Gene function enrichment analysis showed that these IRGs are significantly associated with response to receptor ligand activity. Lasso Cox regression analysis identified 10 genes with the greatest prognostic value. A clinical prognostic model based on six IRGs, which performed well for predicting prognosis, revealed significant associations of patients’ survival with age, sex, stage, tumor, node, and metastasis. Moreover, these findings reflect the infiltration of tumors by various immune cells.

Conclusions

We identified six clinically significant IRGs and incorporated them into a clinical prognostic model with great significance for monitoring and predicting prognosis of ccRCC.

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Cytoreductive Nephrectomy in Patients Presenting With Advanced Disease: Have We Finally Answered the Question?

Shapiro DD, Westerman ME, Karam JA, et al.
Cancer J. Sep/Oct 2020;26(5):382-389.
DOI: 10.1097/PPO.0000000000000470.

Abstract

Determining the appropriate patients for cytoreductive nephrectomy (CN) has evolved with the integration of more effective systemic therapies for patients with metastatic renal cell carcinoma (mRCC). While previously considered to be first-line therapy for mRCC, CN has not demonstrated a significant survival advantage over systemic therapy in more recent randomized trials when compared with targeted therapy. Conversely, multiple observational studies demonstrate a therapeutic benefit for CN. This review synthesizes the current literature regarding patient selection for CN and further evaluates the role of CN in the current era of immune checkpoint inhibitor therapy. With careful patient selection, CN maintains an important role in the management of mRCC patients.

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Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma: A Response-Based Phase II Study (OMNIVORE)

McKay RR, McGregor BA, Xie W, et al.
J Clin Oncol. 2020 Oct 27;JCO2002295.
DOI: 10.1200/JCO.20.02295

Abstract

Purpose

In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473).

Methods

We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B).

Results

Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed.

Conclusions

In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

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