Hypertension and Angiotensin System Inhibitors in Patients with Metastatic Renal Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Derosa L
PROVIDER: S-EPMC5136757 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
Publications
Hypertension and Angiotensin System Inhibitors in Patients with Metastatic Renal Cell Carcinoma.
Derosa Lisa L Izzedine Hassane H Albiges Laurence L Escudier Bernard B
Oncology reviews 20161001 2
Arterial hypertension (HTN) is a class effect of anti-vascular endothelial growth factor (VEGF) therapies, including the monoclonal antibody bevacizumab. Data are conflicting regarding the role of the renin-angiotensin system on angiogenesis and recent data suggest that the use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) is associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used wit ...[more]
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Project description:The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era.We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFN?. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus.In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice.
| S-EPMC4566854 | biostudies-literature
Project description:BackgroundRenin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI.MethodsThis multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR).ResultsOverall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034).ConclusionsRASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients.
| S-EPMC10013974 | biostudies-literature
Project description:BackgroundThe International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the gold standard for risk-stratifying patients with metastatic renal cell cancer (mRCC). We developed a novel risk scoring system for patients with mRCC treated with immune checkpoint inhibitors (ICIs).MethodsWe performed a retrospective analysis of 100 ICI-treated patients with mRCC at Winship Cancer Institute from 2015 to 2018. Several baseline variables were collected, including markers of inflammation, body mass index (BMI), and sites of metastatic disease, and all were considered for inclusion in our risk scoring system. Upon variable selection in multivariable model, monocyte-to-lymphocyte ratio (MLR), BMI, and number and sites of metastases at baseline were used for risk score calculation. Patients were categorized using four-level risk groups as good (risk score = 0), intermediate (risk score = 1), poor (risk score = 2), or very poor (risk score = 3-4). Cox's proportional hazard model and the Kaplan-Meier method were implemented for survival outcomes.ResultsMost patients were male (66%) with clear cell renal cell carcinoma (72%). The majority (71%) received anti-programmed cell death protein-1 monotherapy. Our risk scoring criteria had higher Uno's concordance statistics than IMDC in predicting overall survival (OS; 0.71 vs. 0.57) and progression-free survival (0.61 vs. 0.58). Setting good risk (MLR <0.93, BMI ≥24, and D_Met = 0) as the reference, the OS hazard ratios were 29.5 (95% confidence interval [CI], 3.64-238.9), 6.58 (95% CI, 0.84-51.68), and 3.75 (95% CI, 0.49-28.57) for very poor, poor, and intermediate risk groups, respectively.ConclusionRisk scoring using MLR, BMI, and number and sites of metastases may be an effective way to predict survival in patients with mRCC receiving ICI. These results should be validated in a larger, prospective study.Implications for practiceA risk scoring system was created for patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. The results of this study have significant implications for practicing oncologists in the community and academic setting. Importantly, these results identify readily available risk factors that can be used clinically to risk-stratify patients with metastatic renal cell carcinoma who are treated with immune checkpoint inhibitors.
| S-EPMC7066702 | biostudies-literature
Project description:We conducted this study to determine whether immunoscore system (IS) predicts survival in patients with metastatic renal cell carcinoma (mRCC). A total of 218 mRCC patients treated with sunitinib or sorafenib in Zhongshan Hospital, Fudan University were recruited during 2007-2017, retrospectively. CD8, CD4, Treg, PD-1 and PD-L1 expression were evaluated by immunohistochemical staining of paraffin embedded slide. Kaplan-Meier method and COX regression model were used in survival analyses. Multivariate analyses demonstrated that expressions of CD8, Treg, PD-1 and stromal PD-L1 (sPD-L1) expressions were independent predictive factors for OS, thus IS was established containing these four immunological factors. Subsequent analysis revealed that performance of IS provided good differentiation of OS and PFS. Besides, multivariate analysis identified IS as an independent prognostic factor for OS (p<0.001) and PFS (p=0.002). IS, compared with International mRCC Database Consortium (IMDC) risk model, and provided better prediction ability for OS. Results suggested that IS was a powerful prognostic factor for OS and PFS in patients with mRCC treated with tyrosine kinase inhibitors. And IS can be used as essential supplement to IMDC for outcome prediction in mRCC patients.
| S-EPMC6277607 | biostudies-literature
Project description:Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities.In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ?140?mm?Hg), neutropenia (grade ?2), thrombocytopenia (grade ?2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points.On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand-foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63-0.67) for IMDC classification alone and 0.72 (95% CI: 0.70-0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months).On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model.
| S-EPMC4705883 | biostudies-other
Project description:Renal cell carcinoma (RCC) is one of the most common kidney malignancies. An upgraded comprehension of the molecular biology implicated in the development of cancer has stimulated an increase in research and development of innovative antitumor therapies. The aim of the study was to analyze the medical literature for hypertension and renal toxicities as the adverse events of the vascular endothelial growth factor (VEGF) signaling pathway inhibitor (anti-VEGF) therapy. Relevant studies were identified in PubMed and ClinicalTrials.gov databases. Eligible studies were phase III and IV prospective clinical trials, meta-analyses and retrospective studies that had described events of hypertension or nephrotoxicity for patients who received anti-VEGF therapy. A total of 48 studies were included in the systematic review. The incidence of any grade hypertension ranged from 17% to 49.6%. Proteinuria and increased creatinine levels were ascertained in 8% to 73% and 5% to 65.6% of patients, respectively. These adverse events are most often mild in severity but may sometimes lead to treatment discontinuation. Nephrotoxicity and hypertension are related to multiple mechanisms; however, one of the main disturbances in those patients is VEGF inhibition. There is a significant risk of developing hypertension and renal dysfunction among patients receiving anti-VEGF treatment; however, there is also some evidence that these side effects may be used as biomarkers of response to antiangiogenic agents.
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Project description:BackgroundCabozantinib is an effective treatment for metastatic renal cell carcinoma (mRCC). The international mRCC database consortium (IMDC) criteria is the gold standard for risk stratification in mRCC. We created a risk scoring system specific for mRCC patients treated with cabozantinib.MethodsWe conducted a retrospective review of 87 patients with mRCC treated with cabozantinib at Winship Cancer Institute from 2015 to 2019. Overall survival (OS) and progression free survival (PFS) were used to measure clinical outcomes. Upon variable selection in multivariable analysis (MVA), elevated baseline monocyte-to-lymphocyte ratio (MLR), sarcomatoid histologic component, ECOG PS > 1, and absence of bone metastases were each assigned 1 point. A three-group risk scoring system was then created: low (score=0-1), intermediate (score=2), and high risk (score=3-4). The Cox proportional hazard model and Kaplan-Meier method were used for survival analyses.ResultsThe median age was 62 years-old and the majority were males (71%) with clear-cell RCC (75%). Most (67%) received at least 1 prior line of systemic therapy. High risk and intermediate risk pts had significantly shorter OS (high risk HR: 13.84, p<0.001; intermediate risk HR: 3.50, p = 0.004) and PFS (high risk HR: 7.31, p<0.001; intermediate risk HR: 1.87, p = 0.053) compared to low risk patients in MVA.ConclusionsRCC patients treated with cabozantinib may benefit from specific risk stratification criteria using RCC histology, ECOG PS, sites of metastatic disease, and MLR. These variables are easily accessible in the clinical setting and may be helpful to determine which mRCC patients may benefit from treatment with cabozantinib.
| S-EPMC8405548 | biostudies-literature
Project description:The purpose of this study was to determine the prognostic impact of fat loss after immune checkpoint inhibitor (ICI) treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). Data from 60 patients treated with ICI therapy for metastatic ccRCC were retrospectively analyzed. Changes in cross-sectional areas of subcutaneous fat (SF) between the pre-treatment and post-treatment abdominal computed tomography (CT) images were expressed as percentages and were divided by the interval between the CT scans to calculate ΔSF (%/month). SF loss was defined as ΔSF < -5%/month. Survival analyses for overall survival (OS) and progression-free survival (PFS) were performed. Patients with SF loss had shorter OS (median, 9.5 months vs. not reached; p < 0.001) and PFS (median, 2.6 months vs. 33.5 months; p < 0.001) than patients without SF loss. ΔSF was independently associated with OS (adjusted hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.07-2.07; p = 0.020) and PFS (adjusted HR, 1.57; 95% CI, 1.17-2.12; p = 0.003), with a 5%/month decrease in SF increasing the risk of death and progression by 49% and 57%, respectively. In conclusion, Loss of SF after treatment initiation is a significant and independent poor prognostic factor for OS and PFS in patients with metastatic ccRCC who receive ICI therapy.
| S-EPMC9967473 | biostudies-literature
Project description:The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-alpha 2a (INF-alpha), s.c. interleukin-2 (IL-2) (n=102 pts), (B) s.c. IFN-alpha 2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n=235 pts) or (C) s.c. IFN-alpha 2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n=88 pts). Kaplan-Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count > or = 6500 cells microl(-1), (4) serum lactate dehydrogenase level (LDH) > or = 220 U l(-1), and (5) serum C-reactive protein level (CRP) > or = 11 mg l(-1). Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio=1.9, P<0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio < or = 1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of 27%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials.
| S-EPMC2747541 | biostudies-other
Project description:BackgroundPreclinical studies indicate that the concurrent use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between the use of RAAS inhibitors and outcomes among patients treated with immune checkpoint inhibitors (ICIs).MethodsWe performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients, 5910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3426 were prescribed a RAAS inhibitor during ICI treatment, and 2484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by cancer types.ResultsThoracic cancer (34%) and melanoma (16%) were the most common types of cancer. Those prescribed a RAAS inhibitor were older, more frequently male, and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (hazard ratio (HR):0.92, [95% Confidence Interval (CI):0.85-0.99], P = .032). Patients with gastrointestinal (HR:0.82, [95% CI: 0.67-1.01], P = .057) and genitourinary cancer (HR:0.81, [95% CI:0.64-1.01], P = .067) had a non-statistically significant better overall survival.ConclusionsIn this large retrospective study, patients with hypertension who were concomitantly taking a RAAS inhibitor during ICI therapy had better overall survival. This benefit was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in patients with cancer who receive ICI therapy.
| S-EPMC9618285 | biostudies-literature