Real-world Assessment of Clinical Outcomes in Patients with Metastatic Renal Cell Carcinoma with or Without Sarcomatoid Features Treated with First-line Systemic Therapies.

BACKGROUND AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) patients have been reported to have better outcomes when treated with immunotherapies (IO) compared to targeted therapies (TT). This study aims to evaluate the impact of first-line systemic therapies on survival of mRCC patients with or without sarcomatoid features using real-world data. METHODS: Metastatic RCC patients of International mRCC Database Consortium (IMDC) intermediate or high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system. Patients were classified by initial treatment: (1) targeted therapy (TT) used alone or (2) immunotherapy (IO)-based systemic therapies used in combination of either IO-IO or IO-TT. The inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazard models were used to assess the impact of initial treatment received on overall survival (OS). KEY FINDINGS AND LIMITATIONS: Of the 1202 eligible patients, 791 were treated with TT and 411 with IO combinations. Of the patients, 76% were male, and the majority (91%) had a nephrectomy before systemic therapy. In nonsarcomatoid patients (639 TT and 320 IO patients), treatment with IO was associated with improved OS compared with patients treated with TT (median of 72 vs 48 mo, hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.50-0.80, objective response rate [ORR] of 38.5% for IO and 23.5% for TT). In sarcomatoid patients (152 TT and 91 IO patients), treatment with IO was associated with improved OS (median of 48 vs 18 mo, HR 0.41, 95% CI 0.26-0.64, ORR of 49.5% for IO and 13.8% for TT). Similar results were observed in patients with synchronous metastatic disease only. CONCLUSIONS AND CLINICAL IMPLICATIONS: IO treatment was associated with improved survival in mRCC patients. The magnitude of benefit is increased in patients with sarcomatoid mRCC, consequently, identifying the sarcomatoid status early on could help healthcare providers make a better treatment decision. PATIENT SUMMARY: Metastatic renal cell carcinoma (mRCC) patients of International mRCC Database Consortium intermediate and high risk, diagnosed from January 2011 to December 2022, treated with first-line systemic therapies, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). In this study, treatment with immunotherapy was associated to an improved survival and response rates for mRCC patients with and without sarcomatoid features. The magnitude of benefit is increased in patients with sarcomatoid mRCC.

Socioeconomic determinants of racial disparities in survival outcomes among patients with renal cell carcinoma.

PURPOSE: Racially driven outcomes in cancer are challenging to study. Studies evaluating the impact of race in renal cell carcinoma (RCC) outcomes are inconsistent and unable to disentangle socioeconomic disparities from inherent biological differences. We therefore seek to investigate socioeconomic determinants of racial disparities with respect to overall survival (OS) when comparing Black and White patients with RCC. METHODS: We queried the National Cancer Database (NCDB) for patients diagnosed with RCC between 2004 and 2017 with complete clinicodemographic data. Patients were examined across various stages (all, cT1aN0M0, and cM1) and subtypes (all, clear cell, or papillary). We performed Cox proportional hazards regression with adjustment for socioeconomic and disease factors. RESULTS: There were 386,589 patients with RCC, of whom 46,507 (12.0%) were Black. Black patients were generally younger, had more comorbid conditions, less likely to be insured, in a lower income quartile, had lower rates of high school completion, were more likely to have papillary RCC histology, and more likely to be diagnosed at a lower stage of RCC than their white counterparts. By stage, Black patients demonstrated a 16% (any stage), 22.5% (small renal mass [SRM]), and 15% (metastatic) higher risk of mortality than White patients. Survival differences were also evident in histology-specific subanalyses. Socioeconomic factors played a larger role in predicting OS among patients with SRMs than in patients with metastasis. CONCLUSIONS: Black patients with RCC demonstrate worse survival outcomes compared to White patients across all stages. Socioeconomic disparities between races play a significant role in influencing survival in RCC.

A Cost-effectiveness Analysis Comparing Pembrolizumab-Axitinib, Nivolumab-Ipilimumab, and Sunitinib for Treatment of Advanced Renal Cell Carcinoma.

OBJECTIVES: The US Food and Drug Administration (FDA) approved nivolumab-ipilimumab and pembrolizumab-axitinib as first-line treatments for metastatic, clear-cell, renal cell carcinoma (mRCC) based on results from CheckMate 214 and KEYNOTE-426. Our objective was to compare the adjusted, lifetime cost-effectiveness between nivolumab-ipilimumab, pembrolizumab-axitinib, and sunitinib for patients with mRCC. MATERIALS AND METHODS: A 3-state Markov model was developed comparing nivolumab-ipilimumab and pembrolizumab-axitinib to each other and sunitinib, over a 20-year lifetime horizon from a US medical center perspective. The clinical outcomes of nivolumab-ipilimumab and pembrolizumab-axitinib were compared using matching-adjusted indirect comparison. Costs of drug treatment, adverse events, and utilities associated with different health states and adverse events were determined using national sources and published literature. Our outcome was incremental cost-effectiveness ratio (ICER) using quality-adjusted life years (QALY). One-way and probabilistic sensitivity analyses were conducted. RESULTS: Nivolumab-ipilimumab was the most cost-effective option in the base case analysis with an ICER of $34,190/QALY compared with sunitinib, while the pembrolizumab-axitinib ICER was dominated by nivolumab-ipilimumab and was not cost-effective (ICER=$12,630,828/QALY) compared with sunitinib. The mean total costs per patient for the nivolumab-ipilimumab and pembrolizumab-axitinib arms were $284,683 and $457,769, respectively, compared with sunitinib at $241,656. QALY was longer for nivolumab-ipilimumab (3.23 QALY) than for adjusted pembrolizumab-axitinib (1.99 QALY), which was longer than sunitinib's (1.98 QALY). These results were most sensitive to treatment cost in both groups, but plausible changes did not alter the conclusions. CONCLUSIONS: The base case scenario indicated that nivolumab-ipilimumab was the most cost-effective treatment option for mRCC compared with pembrolizumab-axitinib and sunitinib.

Skeletal muscle radiodensity and visceral adipose tissue index are associated with survival in renal cell cancer - A multicenter population-based cohort study.

INTRODUCTION: Body composition has been associated with disease outcome in several cancer types. Results for localized and metastatic renal cell cancer (RCC) are limited and inconsistent. Our aim was to examine the association between body composition and survival in RCC. METHODS: We conducted a population-based historical cohort study including patients diagnosed with RCC from 2008 to 2012. Diagnostic Computed Tomography images at the third lumbar vertebra (L3) were assessed for skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI) and subcutaneous adipose tissue index (SATI). Clinical data was retrieved from medical records. Multivariable Cox regressions with restricted cubic splines were used to determine hazard ratios (HRs) and 95% confidence intervals (95%CIs) for 10-unit increases in body composition features with overall survival (OS) and recurrence-free survival (RFS). RESULTS: We included 719 stage I-III (of whom 254 (35.3%) died and 148 (21.9%) experienced recurrence) and 320 stage IV RCC patients (of whom 298 (93.1%) died). Median follow-up was 6.35 years (interquartile range; 1.41-8.23). For stage I-III, higher SMD was associated with better OS (men: HR 0.86; 95% CI 0.68-1.08; women: HR 0.69; 95% CI 0.50-0.95). Lower compared to median VATI was associated with worse OS for both men (HR 1.38; 95%CI 1.05-1.83 for VATI = 25) and women (HR 1.67; 95%CI 1.01-2.78 for VATI = 20). For stage IV, higher SMD and higher VATI were associated with better OS among men (HR 0.74; 95% CI 0.59-0.94 and HR 0.93; 95% CI 0.88-0.99, respectively). Results for women were similar but non-significant. No statistically significant associations were found for SMI or SATI. CONCLUSION: Higher SMD and higher VATI were marginally associated with better survival in RCC patients and might be useful for better prognostication. However, the added value to current prognostic scores needs to be investigated.

Quality of life assessment in renal cell carcinoma Phase II and III clinical trials published between 2010 and 2020: a systematic review.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Lay abstract Recent years have seen growing attention toward quality of life (QoL) in medical oncology clinical trials and statistical measurement of this aspect of cancer treatment. Nonetheless, although most clinicians and researchers agree that QoL should represent a fundamental component of clinical trials, the inclusion of QoL results is still inadequate, and our systematic review confirms that implementing the inclusion of QoL remains an urgent need.

The Association Between Race and 5-year Survival in Patients With Clear Cell Renal Cell Carcinoma: A Cohort Study.

OBJECTIVE: To determine if race was associated with 5-year cause-specific survival in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: Outcomes were investigated using the Surveillance Epidemiology and End Results database with data from 13 states between the years 2007-2015. Covariates included age, sex, insurance, marital status, and tumor stage at diagnosis. Patients <18 years old or with missing data for race, survival time or insurance status were excluded. Cox regression models were used to determine associations through hazard ratios (HR) with 95% confidence intervals (CI) and to adjust for covariates. RESULTS: A total of 8421 subjects were included in the analysis. After adjustment, there was no association between race and 5-year cause-specific survival in patients with ccRCC (Black- HR: 0.96, 95%CI: 0.83,1.12; American Indian/Alaskan- HR: 1.01, 95%CI: 0.75,1.36; Asian Pacific Islander- HR: 0.99, 95%CI: 0.82,1.12). Older individuals and those with regional or distant tumors showed an increased hazard of death, while females and insured patients showed decreased hazard. CONCLUSION: Our study found that race was not associated with 5-year cause-specific survival from clear cell renal cell carcinoma. However inferior overall survival in Blacks with RCC has been well demonstrated in the literature. Our findings suggest that differences in survival may not be driven by cause-specific factors such as renal cell carcinoma, but rather social determinants of health which disproportionality affect Black patients. Further studies with more power that incorporate information on income, comorbidities, education status, and access to care are therefore necessary.

Assessment of other-cause mortality in localized renal cell carcinoma patients within 15 years: A population-based analysis.

BACKGROUND AND OBJECTIVE: Five-year other cause mortality (OCM) after nephrectomy for non-metastatic renal cell carcinoma (RCC) should be marginal in properly selected surgical candidates. We examined 5-year OCM rates as a quality of care indicator for patient selection. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results database (1997-2011), we identified 59267 RCC patients treated with either radical (n = 27 804, 46.9%) or partial nephrectomy (n = 31 463, 53.1%). Temporal trends and multivariable Cox regression analyses assessed 5-year OCM. Data were stratified according to age group, year of diagnosis, race, marital status, gender, and socio-economic status. The overall OCM rates for the entire cohort at 5 years of follow-up was 4.7% and decreased from 9.4% to 5.6% over the study span (-3.8%, P < .001). The greatest decrease in 5-year OCM rates over time was recorded in patients >70 years (17.0%-9.6%, slope, -0.6%/y), as well as in African-Americans (12.0-6.2%; slope, -0.3%/y) and in males (8.9%-4.7%; slope, -0.3%, all P < .001). CONCLUSIONS: An important OCM decrease was recorded over the study span. Nonetheless, further improvement may be accomplished, especially in African-Americans, unmarried and older individuals, who exhibited higher OCM rates than others. These three groups may represent ideal targets for better patient selection based on OCM considerations.

Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma.

OBJECTIVE: Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective. METHODS: A partitioned survival model with three states (progression-free, progressed, death) evaluated lifetime costs and quality-adjusted life-years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib, pazopanib and avelumab/axitinib in the overall population; and sunitinib, cabozantinib and nivolumab/ipilimumab in the subgroup with intermediate/poor prognostic risk. Costs of treatments, adverse events and medical resources were estimated. OS, PFS and treatment duration were extrapolated using parametric models fitted to KEYNOTE-426 data and hazard ratios from network meta-analyses. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EuroQol-5 Dimensions-3 Levels data. RESULTS: In the overall population, pembrolizumab/axitinib was associated with incremental cost-effectiveness ratios (ICERs) of $95,725/QALY versus sunitinib and $128,210/QALY versus pazopanib, and was dominant (lower cost, higher effectiveness) versus avelumab/axitinib, with incremental QALY gains of 2.73, 2.40 and 1.80 versus these therapies, respectively. In the intermediate/poor-risk subgroup, base-case ICERs for pembrolizumab/axitinib were $101,030/QALY versus sunitinib, $6989/QALY versus cabozantinib, and $130,934/QALY versus nivolumab/ipilimumab, with incremental QALY gains of 2.62, 1.78 and 1.06 versus these therapies. CONCLUSIONS: In this economic evaluation, pembrolizumab/axitinib was associated with higher life expectancy and QALYs and, based on typical willingness-to-pay thresholds of $150,000-$180,000/QALY, was found cost-effective versus other first-line treatments for advanced RCC in the US.

Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.

BACKGROUND: The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up. METHODS: Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory. RESULTS: Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55-0.80) and PFS (HR, 0.75; 95% CI, 0.62-0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61-0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77-1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46-0.54), and more patients achieved complete response (10.1%-12.8% vs 1.4%-5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports. CONCLUSIONS: NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months' minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response. TRIAL REGISTRATION NUMBER: NCT02231749.

Clinical and economic outcomes of treatment sequences for intermediate- to poor-risk advanced renal cell carcinoma.

Aim: To assess the cost-effectiveness of treatment sequences for patients with intermediate- to poor-risk advanced renal cell carcinoma. Patients & methods: A discrete event simulation model was developed to estimate patients' lifetime costs and survival. Efficacy inputs were derived from the CheckMate 214 and CheckMate 025 studies and network meta-analyses. Safety and cost data were obtained from the published literature. Results: The estimated average quality-adjusted life-years (QALYs) gained was the highest on nivolumab + ipilimumab-initiated sequences (3.6-5.3 QALYs) versus tyrosine kinase inhibitor (TKI)-initiated sequences (2.1-3.7 QALYs). Incremental cost per QALY gained for nivolumab + ipilimumab-initiated sequences was below the willingness-to-pay threshold of $150,000 versus other sequences. Conclusion: Immuno-oncology combination therapy followed by TKIs is cost-effective versus TKI sequences followed by immuno-oncology or sequencing TKIs.

Comparison of Cancer Specific Outcomes following Minimally Invasive and Open Surgical Resection of Early Stage Kidney Cancer from a National Cancer Registry.

PURPOSE: With anecdotal observations of atypical recurrences following minimally invasive surgery and alongside new concerns following cervical cancer surgery, there is a need to evaluate cancer specific outcomes for minimally invasive kidney cancer surgery using national data. We evaluated cancer specific outcomes following minimally invasive surgery vs open surgery for early stage kidney cancer. MATERIALS AND METHODS: We performed a retrospective population based cohort study using data from the SEER (Surveillance, Epidemiology, and End Results) program linked with Medicare claims that included beneficiaries at least 66 years old diagnosed between 2004 and 2013 with early stage, nonurothelial kidney cancer who underwent surgical resection within a year of diagnosis. We compared overall survival, disease specific survival, rate of second kidney cancer surgery and rate of postoperative systemic cancer therapy based on whether surgery was minimally invasive surgery or an open resection. Multivariable regression was used to account for confounders. RESULTS: A total of 5,150 patients were included in analysis and 3,062 (59.5%) underwent minimally invasive surgery. On multivariable analysis minimally invasive surgery was not associated with differences in overall survival (HR 0.94, 95% CI 0.84-1.06) or disease specific survival (HR 0.96, 95% CI 0.83-1.11). Patients treated with minimally invasive surgery were more likely to receive systemic cancer therapy (HR 1.31, 95% CI 1.09-1.59). No difference in the rate of second surgery associated with surgical approach was observed. CONCLUSIONS: Use of minimally invasive surgery for early stage kidney cancer was not associated with differences in overall or disease specific survival, or the rate of second kidney cancer surgery. Patients treated with minimally invasive surgery received more postoperative systemic therapy, which could represent a disparate cancer specific outcome associated with minimally invasive surgery.

Evaluating Partitioned Survival and Markov Decision-Analytic Modeling Approaches for Use in Cost-Effectiveness Analysis: Estimating and Comparing Survival Outcomes.

OBJECTIVE: The objective of this study was to assess long-term survival outcomes for nivolumab and everolimus in renal cell carcinoma predicted by three model structures, a partitioned survival model (PSM) and two variations of a semi-Markov model (SMM), for use in cost-effectiveness analyses. METHODS: Three economic model structures were developed and populated using parametric curves fitted to patient-level data from the CheckMate 025 trial. Models consisted of three health states: progression-free, progressed disease, and death. The PSM estimated state occupancy using an area under-the-curve approach from overall survival (OS) and progression-free survival (PFS) curves. The SMMs derived transition probabilities to calculate patient flow between health states. One SMM assumed that post-progression survival (PPS) was independent of PFS duration (PPS Markov); the second SMM assumed differences in PPS based on PFS duration (PPS-PFS Markov). RESULTS: All models provide a reasonable fit to the observed OS data at 2 years. For estimating cost effectiveness, however, a more relevant comparison is between estimates of OS over the modeling horizon, because this will likely impact differences in costs and quality-adjusted life-years. Estimates of the incremental mean survival benefit of nivolumab versus everolimus over 20 years were 6.6 months (PSM), 7.6 months (PPS Markov), and 7.4 months (PPS-PFS Markov), reflecting non-trivial differences of + 14% and + 11%, respectively, compared with PSM. CONCLUSIONS: The evidence from this study and previous work highlights the importance of the assumptions underlying any model structure, and the need to validate assumptions regarding survival and the application of treatment effects against what is known about the characteristics of the disease.

Comparative Survival Associated With Use of Targeted vs Nontargeted Therapy in Medicare Patients With Metastatic Renal Cell Carcinoma.

Importance: Targeted therapies for advanced renal cell carcinoma (RCC) have shown increased tolerability and survival advantages over older treatments in clinical trials, but understanding of real-world survival improvements is still emerging. Objective: To compare overall and RCC-specific survival associated with use of targeted vs nontargeted therapy for metastatic RCC. Design, Setting, and Participants: This retrospective cohort study used Surveillance, Epidemiology, and End Results-Medicare data from 2000 to 2013 to examine patients with stage IV (distant) clear cell RCC at the time of diagnosis who received any targeted or nontargeted therapy. A 2-stage residual inclusion model was fitted to estimate the survival advantages of targeted treatments using an instrumental variable approach to account for both measured and unmeasured group differences. Data analyses were conducted from July 24, 2017, to April 4, 2019. Exposures: Targeted therapy (study group) or nontargeted therapy (control group). Main Outcomes and Measures: Overall survival and RCC-specific survival, defined as the interval between the date of first drug treatment and date of death or end of the observation period. Results: The final sample included 1015 patients (mean [SD] age, 71.2 [8.1] years; 392 [39%] women); 374 (37%) received nontargeted therapy and 641 (63%) received targeted therapy. The targeted therapy group had a greater percentage of disabled patients (ie, those <65 years old who were eligible for Medicare because of disability) and older patients (ie, those ≥75 years old) and higher comorbidity index and disability scores compared with the nontargeted therapy group. Unadjusted Kaplan-Meier survival curves showed higher overall survival for targeted vs nontargeted therapy (log-rank test, χ21 = 5.79; P = .02); median survival was not statistically significantly different (8.7 months [95% CI, 7.3-10.2 months] vs 7.2 months [95% CI, 5.8-8.8 months]; P = .14). According to the instrumental variable analysis, the median overall survival advantage was 3.0 months (95% CI, 0.7-5.3 months), and overall survival improvements associated with targeted therapy vs nontargeted therapy were statistically significant: 8% at 1 year (44% [95% CI, 39%-50%] vs 36% [95% CI, 30%-42%]; P = .01), 7% at 2 years (25% [95% CI, 20%-30%] vs 18% [95% CI, 13%-23%]; P = .009), and 5% at 3 years (15% [95% CI, 11%-19%] vs 10% [95% CI, 6%-13%]; P = .01). Receipt of targeted therapy was associated with a lower hazard of death compared with nontargeted therapy (overall survival hazard ratio, 0.78 [95% CI, 0.65-0.94]; RCC-specific survival hazard ratio, 0.77 [95% CI, 0.62-0.96]). Conclusions and Relevance: Targeted therapies were associated with modest survival advantages despite a treatment group with more medical complexity, likely reflecting appropriateness for an expanded population of patients. As advances in cancer treatment continue, rigorous methods that account for unobserved confounders will be needed to evaluate their real-world impact on outcomes.

Cost-Effectiveness Analysis of Sunitinib versus Interferon-Alfa for First-Line Treatment of Advanced and/or Metastatic Renal Cell Carcinoma in Singapore.

OBJECTIVES: This study was conducted to evaluate the cost-effectiveness of sunitinib versus interferon-alfa for the treatment of advanced and/or metastatic renal cell carcinoma (RCC) in Singapore. METHODS: A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from a healthcare payer perspective over a 10-year time horizon. Survival curves from the pivotal trial of sunitinib versus interferon-alfa were extrapolated beyond the trial period to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from local public healthcare institutions. The sunitinib dose in the model reflected local prescribing practices whereby a combination of 50 mg (28 percent) and 37.5 mg (72 percent) strengths are used. RESULTS: The base-case analysis comparing sunitinib versus interferon-alfa resulted in an incremental cost effectiveness ratio (ICER) of SGD191,061 (USD139,757) per quality-adjusted life-year gained. Sensitivity analysis demonstrated that the ICER was most sensitive to variations in the utility value assumed for the progression-free health state and the price of sunitinib. CONCLUSIONS: In the absence of any price reduction, sunitinib had an exceedingly high ICER and was not considered a cost-effective use of healthcare resources in Singapore's context for the first-line treatment of advanced RCC. The findings from our evaluation will be useful to inform local healthcare decision making and resource allocations for tyrosine kinase inhibitors when appraised alongside comparative clinical effectiveness data and payer affordability considerations.

Personalized Treatment for Small Renal Tumors: Decision Analysis of Competing Causes of Mortality.

Purpose To compare the effectiveness of personalized treatment for small (≤4 cm) renal tumors versus routine partial nephrectomy (PN), accounting for various competing causes of mortality. Materials and Methods A state-transition microsimulation model was constructed to compare life expectancy of management strategies for small renal tumors by using 1 000 000 simulations in the following ways: routine PN or personalized treatment involving percutaneous ablation for risk factors for worsening chronic kidney disease (CKD), and otherwise PN; biopsy, with triage of renal cell carcinoma (RCC) to PN or ablation depending on risk factors for worsening CKD; active surveillance for growth; and active surveillance when MRI findings are indicative of papillary RCC. Transition probabilities were incorporated from the literature. Effects of parameter variability were assessed in sensitivity analysis. Results In patients of all ages with normal renal function, routine PN yielded the longest life expectancy (eg, 0.67 years in 65-year-old men with nephrometry score [NS] of 4). Otherwise, personalized strategies extended life expectancy versus routine PN: in CKD stages 2 or 3a, moderate or high NS, and no comorbidities, MRI guidance for active surveillance extended life expectancy (eg, 2.60 years for MRI vs PN in CKD 3a, NS 10); and with Charlson comorbidity index of 1 or more, biopsy or active surveillance for growth extended life expectancy (eg, 2.70 years for surveillance for growth in CKD 3a, NS 10). CKD 3b was most effectively managed by using MRI to help predict papillary RCC for surveillance. Conclusion For patients with chronic kidney disease and small renal tumors, personalized treatment selection likely extends life expectancy. © RSNA, 2019 Online supplemental material is available for this article.

The Development of Brain Metastases in Patients with Renal Cell Carcinoma: Epidemiologic Trends, Survival, and Clinical Risk Factors Using a Population-based Cohort.

BACKGROUND: The incidence of brain metastases (BM) in patients with renal cell carcinoma (RCC) is hypothesized to have increased in the last 2 decades. OBJECTIVE: To define incidence trends according to patient and clinical characteristics, to identify risk factors, and to describe outcomes of patients with BM for RCC. DESIGN, SETTING, AND PARTICIPANTS: Patients diagnosed with RCC between the years 2010 and 2013 within the Surveillance, Epidemiology, and End Results database. An external validation was also considered using patients diagnosed with RCC between 2010 and 2012 within the National Cancer Database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence proportions of BM were calculated. Risk factors correlated with BM at diagnosis were identified via a 1000-bootstrap corrected multivariable logistic regression model. A risk model was then developed and evaluated using measures of predictive accuracy. Overall survival was examined using Cox regression analyses. RESULTS AND LIMITATIONS: The overall incidence proportions of BM at RCC diagnosis was 1.51% (95% confidence interval: 1.39-1.64%). White/other race, clear cell histology, and sarcomatoid differentiation, T2-4 disease, tumor dimension >10 cm, and N+ disease were significantly associated with BM at RCC diagnosis, and retained within the final prediction model. A risk score was created based on these variables (c-index: 0.803). BM at RCC diagnosis occurred in 0.5%, 3.6%, and 7.7% of patients categorized as low risk, intermediate risk, and high risk. Patients with BM were more likely to succumb to any death than those without BM at diagnosis (median overall survival: 6.4 mo vs not reached, respectively, adjusted hazard ratio: 1.87, 95% confidence interval: 1.67-2.08, p < 0.001). The real incidence of BM at RCC diagnosis is likely underestimated given that the observed rate likely reflects patients who presented with symptoms. CONCLUSIONS: Patients with BM at RCC have poor oncological outcomes. We have characterized the epidemiology of BM at RCC diagnosis and developed a clinical risk model for the purpose of predicting the development of BMs in patients diagnosed with a cortical renal mass. PATIENT SUMMARY: In this report we examined recent proportions of patients with brain metastases at kidney cancer diagnosis in a large community database originating from the US. We developed a model that may be used during routine clinical practice to predict brain metastases. The urologic-oncological community may consider baseline imaging for brain metastases in patients without any symptoms but at high risk of having brain metastases according to the risk model. However, the proposed model certainly needs further testing and validation in the clinical setting. Future studies on brain metastases survival and treatment options are also needed.

Assessment of the Role of Everolimus Therapy in Patients with Renal Cell Carcinoma Based on Daily Routine and Recent Research Results.

Everolimus is indicated for adults with metastatic renal cell carcinoma (mRCC) after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitors (TKI). Currently, the therapeutic applicability of EVE has been changing. Multicenter evaluation of efficacy and safety of everolimus in daily routine and definition of patient characteristics with favorable outcome. Data of 165 patients from 9 oncology institutes in Hungary were analyzed retrospectively. Everolimus therapy was used after one TKI in 10 mg starting dose. Physical and laboratory examinations and imaging tests were performed monthly and every 3 months, respectively. Median progression-free survival (PFS) was 5.4 months. Median overall survival (OS) was 16.2 months. PFS and OS results were more favorable in patients with ECOG 0-1 (pPFS = 0.033, pOS = 0.008) and after >9 months of TKI therapy (pPFS = 0.019, pOS = 0.045). Survival was longer in nonanemic patients with ECOG 0-1 than in anemic patients with ECOG 2-3, 30.9 and 7.7 months, respectively (p = 0.029). Dose reduction and treatment delay was required in 6.2% and 8.9% of patients, respectively. Common adverse events were exanthema, edema, stomatitis, anemia, and abnormal kidney functions and glucose levels. Results of this study show that everolimus is safe and efficacious in a real-world setting. Everyday practice showed that nonanemic patients with good performance status receiving TKI therapy for >9 months are favorable candidates for this treatment. Despite the efficiency of novel, registered drugs, everolimus still plays an important role during and after second-line therapy for mRCC when availability of modern remedies is limited.

Comprehensive assessment gene signatures for clear cell renal cell carcinoma prognosis.

There are many prognostic gene signature models in clear cell renal cell carcinoma (ccRCC). However, different results from various methods and samples are hard to contribute to clinical practice. It is necessary to develop a robust gene signature for improving clinical practice in ccRCC.A method was proposed to integrate least absolute shrinkage and selection operator and multiple Cox regression to obtain mRNA and microRNA signature from the cancer genomic atlas database for predicting prognosis of ccRCC. The gene signature model consisted by 5 mRNAs and 1 microRNA was identified. Prognosis index (PI) model was constructed from RNA expression and median value of PI is used to classified patients into high- and low-risk groups.The results showed that high-risk patients showed significantly decrease survival comparison with low-risk groups [hazard ratio (HR) =7.13, 95% confidence interval = 3.71-13.70, P < .001]. As the gene signature was mainly consisted by mRNA, the validation data can use transcriptomic data to verify. For comparison of the performance with previous works, other gene signature models and 4 datasets of ccRCC were retrieved from publications and public database. For estimating PI in each model, 3 indicators including HR, concordance index , and the area under the curve of receiver operating characteristic for 3 years were calculated across 4 independent datasets.The comparison results showed that the integrative model from our study was more robust than other models via comprehensive analysis. These findings provide some genes for further study their functions and mechanisms in ccRCC tumorigenesis and malignance, and may be useful for effective clinical decision making of ccRCC patients.

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.