Upfront Cytoreductive Nephrectomy Research Articles

Is it time to reconsider the role of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma?

Is it time to reconsider the role of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma?

Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study).

About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS)and overall survival(OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: An analysis of the TriNetX database.

The role of upfront cytoreductive nephrectomy remains debatable in the present era of tyrosine kinase inhibitors and immune checkpoint inhibitors. Here, we aimed to evaluate the outcomes of metastatic renal cell carcinoma patients treated with upfront CN and modern systemic therapies. Using the TriNetX network database, we identified patients, in the period from 2008 to 2022, who were diagnosed with metastatic renal cell carcinoma, receiving first-line systemic therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors. Their overall survivals were evaluated using the Kaplan-Meier method as well as multivariable regressions. We identified 11,094 patients with metastatic renal cell carcinoma. Of them, 2,914 (43%) patients in the tyrosine kinase inhibitor cohort (n = 6,779), and 1,884 (43.7%) in the immune checkpoint inhibitors cohort (n = 4315) underwent upfront cytoreductive nephrectomy. Those receiving upfront cytoreductive nephrectomy showed survival advantages with either tyrosine kinase inhibitor (Hazard ratio 0.722, 95% Confidence interval 0.67-0.73, p<0.001) or immune checkpoint inhibitors (Hazard ratio 65.1, 95% Confidence interval 0.59-0.71, p<0.001). In multivariable analysis, upfront cytoreductive nephrectomy was a factor for improved OS in both cohorts: tyrosine kinase inhibitors (Hazard ratio 0.623, 95% Confidence interval 0.56-0.694, p<0.001) and immune checkpoint inhibitors cohort (Hazard ratio 0.688, 95% Confidence interval 0.607-0.779, p<0.001). Upfront cytoreductive nephrectomy was associated with an improved overall survival for patients with metastatic renal cell carcinoma receiving either first-line tyrosine kinase inhibitors or immune checkpoint inhibitors. Our results support a clinical role of upfront cytoreductive nephrectomy in the modern era.

Systemic and surgical treatment in renal cell carcinoma: Does timing matter?

417 Background: Today, targeted systemic therapy is standard 1st line treatment of advanced/metastatic renal cell carcinoma (aRCC). Upfront cytoreductive nephrectomy (CN) has been an important treatment option. Recently its role is under debate, especially in combination with the new 1st line treatments. Our study evaluated the current relevance of initial surgical intervention and the role of inductive systemic therapy in aRCC. Methods: We included 33 patients with aRCC from the University Hospitals in Essen and Münster initiating 1st line treatment from 03/18 to 01/23 pre or post surgery. We retrospectively formed two cohorts, either CN followed by systemic therapy (cohort 1; 13 patients) or vice versa (cohort 2; 20 patients). Patients received either Ipilimumab/Nivolumab (Ipi/Nivo) (42.4%) or a checkpoint inhibitor and tyrosine kinase inhibitor (CPI/TKI) combination (57.6%). Progression-free survival (PFS) was estimated with Kaplan-Meier-method from initiation of systemic therapy or CN to progression or death. In Cohort 2, we additionally analyzed the radiologic response of the primary measured by change of the longest diameter. The radiographic response was analysed according to RECIST1.1. Results: Patients’ age ranged from 44 to 80 years with a median of 63 years. Intermediate and poor prognosis occurred in 61.3% and 38.7% of cases. The two cohorts did not differ significantly regarding baseline characteristics. Median PFS was 8 vs. 23 months (p=0.03) in cohort 1 (95% CI 0.9-15.1) compared to cohort 2 (95% CI 18.8-27.2). In cohort 2 the time between start of systemic therapy and surgery was in median 8.5 months (95% CI 3.3-21.1), the primary had a median diameter of 10.7 cm (95% CI 4.5-13.3). Median reduction of the primary was in total 32.2%, 28.9% in the Ipi/Nivo and 34.7% in the CPI/TKI group (p=0.74). In seven patients (35%) response led to modification of the surgical approach, enabling partial instead of radical nephrectomy. Conclusions: The sequence of systemic therapy followed by surgery was associated with a significant PFS benefit. In addition, prior systemic therapy led to a primary reduction and better operability, in some cases even to kidney sparing surgery. Major limitation is the retrospective nature of our analysis and a potential selection bias. However, the sequence of prior systemic therapy followed by surgery in aRCC was associated with notably better outcomes.

Characterization of Patients with Metastatic Renal Cell Carcinoma Undergoing Deferred, Upfront, or No Cytoreductive Nephrectomy in the Era of Combination Immunotherapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

BackgroundThe role of cytoreductive nephrectomy (CN) has not yet been well characterized in the era of combination immunotherapy. ObjectiveTo evaluate characteristics and outcomes for patients with metastatic renal cell carcinoma (mRCC) who received immuno-oncology (IO)-based combination therapy according to CN status. Design, setting, and participantsUsing the International mRCC Database Consortium (IMDC), patients with mRCC who received frontline IO-based combinations were included. Upfront CN was defined as CN up to 3 mo before diagnosis of metastatic disease but before systemic therapy initiation. Deferred CN was defined as CN after systemic therapy initiation. Outcomes measurements and statistical analysisOverall survival (OS) from initiation of systemic therapy was estimated via Cox proportional-hazards regression. A 12-mo landmark time and a time-varying covariate for CN status were used to mitigate potential bias. Results and limitationsOf the 385 patients eligible for landmark analysis, 24, 182, and 179 underwent deferred CN, upfront CN, and no CN, respectively. Patients in the no CN subgroup were older (63 yr vs 57 yr in the deferred CN subgroup and 60 yr in the upfront CN subgroup; p = 0.001) and a higher proportion had bone metastases (44% vs 26% in the deferred CN subgroup and 23% in the upfront CN subgroup; p < 0.001). A lower proportion of patients in the upfront CN subgroup had IMDC poor risk (23% vs 43% in the no CN subgroup and 47% in the deferred CN subgroup; p < 0.001). On multivariable analysis, CN receipt was an independent favorable prognostic factor (hazard ratio 0.45, 95% confidence interval 0.26–0.78; p = 0.005). The study is limited by the lack of randomization and its retrospective nature. ConclusionsDespite changes in practice patterns with the advent of novel therapeutic agents, CN may still serve as an effective surgical intervention in carefully selected patients. Patient summaryFor patients with metastatic kidney cancer, surgery to remove the primary tumor was traditionally the treatment of choice, but immunotherapy drugs are now another option for these patients. We analyzed data for contemporary patients with metastatic kidney cancer who received combination immunotherapy as their first treatment. We found that in selected patients receiving immunotherapy, surgery to remove the primary tumor as well can result in better prognosis.

Comparison of upfront versus deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving systemic therapy: A systematic review and meta-analysis.

This study aimed to conduct a pooled analysis to compare the outcomes of patients with metastatic renal cell carcinoma (mRCC) who received presurgical systemic therapy (ST; including immunotherapy and/or targeted therapy) followed by cytoreductive nephrectomy (deferred CN; dCN) with those who underwent upfront CN (uCN) followed by ST. The present study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A comprehensive search was conducted in PubMed, Embase, Web of Science, Scopus, and Cochrane Library database to identify eligible comparative studies up to April 2023. To evaluate their relevance, pooled hazard ratio (HR) with 95% confidence intervals (CIs) were calculated. A total of 3157 patients were included in nine studies. The dCN group was observed to be correlated with superior overall survival (OS) compared to the uCN group (HR=0.71, 95% CI 0.57-0.89, P=0.003). Moreover, we conducted subgroup analyses according to the type of ST, sample size, gender, age, and risk score, and observed similar outcomes for OS across most subgroups. The results of this study demonstrated that dCN may be associated with improved OS compared to uCN in patients with mRCC receiving ST. However, no significant differences were found between uCN and dCN groups in the immunotherapy-based combinations subgroup. Further research is needed to confirm these results.

The impact of primary region resection on the therapeutic outcome of combination regimens for metastatic renal cell carcinoma.

The present study aimed to clarify the relationship between the therapeutic outcome of combination regimens, including immune checkpoint inhibitors (ICIs) and/or tyrosine kinase inhibitors (TKIs), and cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC). The present study retrospectively assessed the association between treatment efficacy and prognosis with or without CN, and the timing of CN in 151 patients treated with combination regimens for mRCC who were categorized as intermediate/poor risk. The first-line regimens included the ICI-ICI and ICI-TKI regimens in 98 and 53 cases, respectively. In patients with recurrence after radical surgery (n=66), the 50% PFS times of the ICI-ICI and the ICI-TKI groups were 33.6 months and not reached (NR) (P=0.4032), respectively, and the 50% OS times were 53.7 months and NR (P=0.6886), respectively. Among the 38 patients with metastasis from the initial diagnosis who underwent upfront CN, the 50% PFS times of the ICI-ICI and the ICI-TKI groups were 10.5 and 8.2 months (P=0.5806), respectively, and the 50% OS times were NR and 15.8 months (P=0.0587), respectively. Among the 51 patients who did not receive upfront CN, the 50% PFS time of the ICI-TKI group was significantly higher than that in the ICI-ICI group (4.1 months and NR, respectively; P=0.0210), and the 50% OS times were 29.8 months and NR (P=0.7343), respectively. In conclusion, according to the analysis of real-world data, good therapeutic efficacy can be achieved with any regimen in patients with recurrence after radical surgery. In addition, improved results could be achieved through treatment with ICI-TKI in patients without upfront CN.

Re: Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium

Re: Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium

PD17-04 THE ROLE OF CYTOREDUCTIVE NEPHRECTOMY WITH IMMUNE CHECKPOINT INHIBITOR THERAPIES IN METASTATIC RENAL CELL CARCINOMA MURINE MODEL

You have accessJournal of UrologyCME1 Apr 2023PD17-04 THE ROLE OF CYTOREDUCTIVE NEPHRECTOMY WITH IMMUNE CHECKPOINT INHIBITOR THERAPIES IN METASTATIC RENAL CELL CARCINOMA MURINE MODEL Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Se Mi Park, and Won Sik Ham Jee Soo ParkJee Soo Park More articles by this author , Myung Eun LeeMyung Eun Lee More articles by this author , Won Sik JangWon Sik Jang More articles by this author , Jongchan KimJongchan Kim More articles by this author , Se Mi ParkSe Mi Park More articles by this author , and Won Sik HamWon Sik Ham More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Since CARMENA trial found non-inferiority of sunitinib alone, the contemporary role of cytoreductive nephrectomy (CN) has been significantly downsized. However, updated CARMENA trial results demonstrated certain subsets with metastatic renal cell carcinoma (mRCC) may still benefit from CN. We tried to assess the role of CN in combination with immune checkpoint inhibitor (ICI) from the perspective tumor immune microenvironment (TIME). METHODS: Low- and high-tumor burden pulmonary metastatic orthotopic murine mRCC models have been developed. Anti-PD-1 and anti-CTLA-4 antibodies were systemically injected through the peritoneum every 3 days. Renca implanted kidney was removed in the CN performed group. For the upfront CN plus ICI group, CN was performed 1 day before the ICI, while CN was performed 5 days after ICI for the deferred CN plus ICI group. The remodeling of the TIME was determined using immunofluorescence analysis. RESULTS: Low- and high-tumor burden murine mRCC models have been successfully developed with statistically significant difference in median survival (p<0.05). In low-tumor burden model (Figure 1A), upfront CN plus ICI group demonstrated significantly better survival outcomes compared to deferred CN plus ICI group. In high-tumor burden model (Figure 1B), similar results were shown as low-tumor burden model, except no significant survival difference between ICI only and CN only group, and between upfront CN plus ICI and deferred CN plus ICI group. Immunofluorescence analysis demonstrated that CN modulate TIME by increasing M1 tumor-associated macrophage (TAM) and at the same time decreasing M2 TAM (Figure 2). CONCLUSIONS: This study is the first animal study to demonstrate the role of CN in combination with ICI. We have shown that the CN has certain role in the immune-oncology (IO) era and was associated with improved survival by the regulation of M1 and M2 TAM. CN also regulated myeloid-derived suppressor cells and regulatory T cells in combination with ICIs although not to be significant in our study. Source of Funding: This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI17C1095], and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number: 2019R1A2C1002863 and 2022R1A2C2003831] © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e496 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jee Soo Park More articles by this author Myung Eun Lee More articles by this author Won Sik Jang More articles by this author Jongchan Kim More articles by this author Se Mi Park More articles by this author Won Sik Ham More articles by this author Expand All Advertisement PDF downloadLoading ...

The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in the targeted therapy and immunological therapy era: a systematic review and meta-analysis.

The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) remains controversial. In addition, several unanswered questions regarding the use of CN remain: Can CN provide survival benefits for patients with mRCC? Where do we place CN in the treatment sequence paradigm among patients with mRCC? How do we best stratify patients with mRCC for CN therapy? A search strategy was conducted in the PubMed, Embase, and Web of Science databases. Studies were included only in the English language. The risk of bias assessment was made by using ROBINS-I (Risk of Bias in Nonrandomized Studies of Interventions) and RoB 2 (Risk of Bias 2) tools. The expected outcomes were analyzed by meta-analyses with the fixed-effects model or random effects model, including overall survival (OS) and progression-free survival (PFS). The measure of effect was the hazard ratio (HR) with a 95% CI, and sensitivity analysis was conducted to assess the reliability of the final results. A total of 30 studies were included in the qualitative analysis. The HR for OS was 0.55 (95% CI, 0.50-0.61), and PFS was 0.72 (95% CI, 0.66-0.80), favoring CN compared with no CN. The upfront CN plus targeted therapy (TT) group had superior OS (HR, 0.57; 95% CI, 0.51-0.64) compared with the TT alone group. Furthermore, upfront CN plus systemic therapy (ST) was associated with numerically inferior OS compared with ST plus deferred CN in patients with mRCC (HR, 1.31; 95% CI, 0.98-1.74). Finally, the leave-one-out test of sensitivity analysis indicated that the results of this meta-analysis were stable and reliable in the overall HR estimates for these survival outcomes. First, CN was associated with better survival than no CN in patients with mRCC. Second, the combination of upfront CN and TT may lead to superior survival outcomes compared to TT alone in patients with mRCC. Survival outcomes were similar between the upfront CN+ST group and the ST+deferred CN group in patients with mRCC. Exact patient selection based on baseline prognostic factors is needed to promise maximal survival for patients with mRCC.

PD24-01 THE SELECTION FOR CYTOREDUCTIVE NEPHRECTOMY (SCREEN) SCORE: SURGICAL RISK STRATIFICATION INTEGRATING RADIOGRAPHIC FEATURES

You have accessJournal of UrologyCME1 Apr 2023PD24-01 THE SELECTION FOR CYTOREDUCTIVE NEPHRECTOMY (SCREEN) SCORE: SURGICAL RISK STRATIFICATION INTEGRATING RADIOGRAPHIC FEATURES Daniel Shapiro, Jose Karam, Viraj Master, Philippe Spiess, Jay Raman, Wade Sexton, Logan Zemp, Dattatraya Patil, Kate Lauer, Glenn Allen, Surena Matin, and E. Jason Abel Daniel ShapiroDaniel Shapiro More articles by this author , Jose KaramJose Karam More articles by this author , Viraj MasterViraj Master More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Jay RamanJay Raman More articles by this author , Wade SextonWade Sexton More articles by this author , Logan ZempLogan Zemp More articles by this author , Dattatraya PatilDattatraya Patil More articles by this author , Kate LauerKate Lauer More articles by this author , Glenn AllenGlenn Allen More articles by this author , Surena MatinSurena Matin More articles by this author , and E. Jason AbelE. Jason Abel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003302.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patient selection for cytoreductive nephrectomy (CN) is critical yet few studies incorporate tumor burden into decision making. This study developed a prognostic model to improve CN selection by integrating radiologic features with known prognostic factors. METHODS: Consecutive mRCC patients treated with upfront CN at 5 institutions from 2006-2017 were included. Preoperative axial imaging was analyzed for measures of tumor burden including number of sites, total metastatic tumor burden (sum of metastatic lesions’ maximum diameter) and maximum primary tumor diameter. Univariable/multivariable Cox models were used to evaluate known prognostic variables associations with overall survival, and the SCREEN model was constructed using independently predictive preoperative variables. This model was compared to the IMDC model for predictive accuracy and clinical utility. RESULTS: A total of 914 mRCC patients were treated with upfront CN during the study period. Seven independently predictive variables used in the SCREEN score included: number of metastatic sites ≥3, total cm of metastatic tumor burden ≥5 cm, bone metastasis, systemic symptoms, low serum hemoglobin, low serum albumin, and neutrophil to lymphocyte ratio ≥4. Risk groups were created based on number of risk factors (Figure 1). The SCREEN model demonstrated improved survival discrimination compared to the IMDC risk groups. When evaluating early mortality (death ≤12 months from CN), predictive accuracy measured by the area under the ROC curve was 0.76 for SCREEN compared to 0.55 for the IMDC model. Decision curve analysis showed that the SCREEN model improved decision making beyond IMDC score for threshold probabilities of early mortality between 15-70% (Figure 2). CONCLUSIONS: The SCREEN model integrates radiographic measurements for mRCC patients, which was associated with improved predictive accuracy. These findings should be validated further in independent cohorts. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e721 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Shapiro More articles by this author Jose Karam More articles by this author Viraj Master More articles by this author Philippe Spiess More articles by this author Jay Raman More articles by this author Wade Sexton More articles by this author Logan Zemp More articles by this author Dattatraya Patil More articles by this author Kate Lauer More articles by this author Glenn Allen More articles by this author Surena Matin More articles by this author E. Jason Abel More articles by this author Expand All Advertisement PDF downloadLoading ...

PD43-11 IMPACT OF CYTOREDUCTIVE NEPHRECTOMY ON PATIENT REPORTED OUTCOMES

You have accessJournal of UrologyCME1 Apr 2023PD43-11 IMPACT OF CYTOREDUCTIVE NEPHRECTOMY ON PATIENT REPORTED OUTCOMES Daniel Shapiro, Viraj Master, Juliana Craig, Dattatraya Patil, Tudor Borza, Glenn Allen, Kyle Richards, David Jarrard, and E. Jason Abel Daniel ShapiroDaniel Shapiro More articles by this author , Viraj MasterViraj Master More articles by this author , Juliana CraigJuliana Craig More articles by this author , Dattatraya PatilDattatraya Patil More articles by this author , Tudor BorzaTudor Borza More articles by this author , Glenn AllenGlenn Allen More articles by this author , Kyle RichardsKyle Richards More articles by this author , David JarrardDavid Jarrard More articles by this author , and E. Jason AbelE. Jason Abel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003353.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: One goal of cytoreductive nephrectomy (CN) is to improve patients’ quality of life, but few studies have used validated patient reported outcomes (PROs) metrics to quantify the benefit of CN. The NCCN FKSI-19 is a validated 19-item questionnaire that measures tumor-specific PROs in patients with kidney cancer. This study evaluated changes in PROs in mRCC patients before and after treatment with CN using the FKSI-19 instrument. METHODS: Patients undergoing upfront CN were recruited at two institutions over two years to complete FKSI-19 forms within 30 days preoperatively and 4-6 weeks postoperatively. The FKSI-19 score ranges from 0-76 with higher scores indicating fewer symptoms. The FKSI-19 contains subdomains including disease related symptoms (DRS), DRS-emotional (DRS-E), DRS-physical (DRS-P) and functional wellbeing (FWB). Wilcoxon matched-pairs signed rank test and Fisher’s exact test were used to compare pre- and postoperative scores. Clinically meaningful improvements in FKSI-19 score were considered if the score increased ≥5 points postoperatively based on prior studies. Logistic regression was used to determine variables associated with meaningful improvements in FKSI scores. RESULTS: A total of 25 patients completed a pre and postop FKSI. Median preop FKSI was 57 (IQR 47-63) and postop 59 (IQR 51-64) (p=0.2) with a median change of+3 points. Tumor size, gender, surgical approach (open vs. laparoscopic), age, and race were not associated with change in FKSI postoperatively (p>0.05 for all). Among the domains, the DRS-E score, which ranges from 0-4, significantly improved postop (median 2 vs 3, p<0.001), indicating patients were less worried their cancer would worsen after CN. 11/25 (44%) patients had meaningful improvements in postop FKSI. Preop FKSI score was inversely associated with meaningful improvements in postop FKSI (OR 0.89 95%CI 0.8-0.96, p=0.02). The patient with the largest improvement in FKSI score was the most symptomatic preoperatively (Figure 1). CONCLUSIONS: Patients had significantly less worry about cancer progression after CN. Patients that had the most improvement in PROs tended to be more symptomatic prior to CN. This study is limited by variability in timing of the postop FKSI. Continued prospective evaluation of CN PROs will help define which patients are most likely to benefit from CN. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1122 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Shapiro More articles by this author Viraj Master More articles by this author Juliana Craig More articles by this author Dattatraya Patil More articles by this author Tudor Borza More articles by this author Glenn Allen More articles by this author Kyle Richards More articles by this author David Jarrard More articles by this author E. Jason Abel More articles by this author Expand All Advertisement PDF downloadLoading ...

Cytoreductive Nephrectomy for Patients with Metastatic Sarcomatoid and/or Rhabdoid Renal Cell Carcinoma Treated with Immune Checkpoint Therapy

BackgroundRenal cell carcinoma (RCC) with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is a highly aggressive tumor with a poor prognosis. Immune checkpoint therapy (ICT) has shown significant treatment efficacy in this subtype. There remains uncertainly regarding the role of cytoreductive nephrectomy (CN) for patients with metastatic RCC (mRCC) with S/R who received ICT. ObjectiveHere, we report the outcomes with ICT for patients with mRCC and S/R dedifferentiation by CN status. Design, setting, and participantsA retrospective review was conducted of 157 patients with sarcomatoid, rhabdoid, or sarcomatoid plus rhabdoid dedifferentiation who received an ICT-based regimen at two cancer centers. InterventionCN performed at any time point; nephrectomy with curative intent was excluded. Outcome measurements and statistical analysisICT treatment duration (TD) and overall survival (OS) from ICT initiation were recorded. To address the immortal time bias, a time-dependent Cox regression model was generated that accounted for confounders identified by a directed acyclic graph as well as a time-dependent nephrectomy variable. Results and limitationsA total of 118 patients underwent CN, and of them, 89 underwent upfront CN. The results did not contradict the supposition that CN does not improve ICT TD (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.65–1.47, p = 0.94) or OS from ICT initiation (HR 0.79, 95% CI 0.47–1.33, p = 0.37). In patients who underwent upfront CN compared with those who did not undergo CN, there was no association with ICT duration or OS (HR 0.61, 95% CI 0.35–1.06, p = 0.08). A detailed clinical summary of 49 patients with mRCC and rhabdoid dedifferentiation is provided. ConclusionsIn this multi-institutional cohort of mRCC with S/R dedifferentiation treated with ICT, CN was not significantly associated with improved TD or superior OS when accounting for the lead time bias. There appears to be a subset of patients who derive meaningful benefit from CN, so improved tools for stratification prior to CN are needed to optimize outcomes. Patient summaryImmunotherapy has improved outcomes for patients with metastatic renal cell carcinoma (mRCC) who have sarcomatoid and/or rhabdoid (S/R) dedifferentiation, which is an aggressive and uncommon feature; yet, the utility of a nephrectomy in this setting is unclear. We found that nephrectomy did not significantly improve survival or time on immunotherapy for these patients with mRCC and S/R dedifferentiation; yet, there may be a subset of patients who benefit from this surgical approach.

Phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/nivolumab for metastatic kidney cancer (CYTOSHRINK).

TPS750 Background: Randomized data from the interferon era demonstrated survival benefits of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN in most IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in mRCC now includes multiple first-line doublet combination immunotherapy approvals. The Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and durable objective responses with ipilimumab and nivolumab (I/N) compared to sunitinib. However, patients with a primary kidney lesion in situ appeared to have less benefit than patients with prior nephrectomy. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. We hypothesize that SBRT to the primary kidney mass will enhance the efficacy of I/N compared to standard of care I/N alone in this unique subset of de novo mRCC patients. We also hypothesize that the combination of SBRT and I/N will lead to upregulation of key components of immune modulation as well as unique perturbation of the host gut microbiome compared to I/N alone. Methods: This phase II trial randomizes untreated mRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven mRCC (any histology) and IMDC intermediate/poor risk disease. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include: (1) immune and genomic profiling of liquid biopsies; (2) transcriptional profiling of baseline tumor biopsies; and (3) interrogation of the gut microbiome and bacterial functionality. Blood and fecal samples will be prospectively collected at baseline, prior to cycle 2 of each arm, and at time of disease progression or the 12-month mark, whichever comes first. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Trial is enrolling in Canada and Australia. Clinical trial information: NCT04090710 .

Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium

BackgroundThe role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear. ObjectiveTo evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy. Design, setting, and participantsUsing the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy. Outcome measurements and statistical analysisOverall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors. Results and limitationsWe identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor–treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41–0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67–0.78, p < 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study. ConclusionsUpfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors. Patient summaryBefore effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors.

What We Have Learnt from CARMENA and SURTIME and What Should Be Done Differently in Future Trials on Cytoreductive Nephrectomy

Upfront cytoreductive nephrectomy (CN) was the standard treatment for selected patients with metastatic Renal Cell Carcinoma (RCC) in the cytokine era for many years. In the recent ‘targeted therapy era’ it has been re-challenged by both the CARMENA and SURTIME trials. As first-line therapy for treatment-naive metastatic clear-cell RCC has now changed to immune checkpoint inhibitor combination therapy (ICI), and previous studies concerning CN were built in the targeted therapy era, the role and sequence of CN needs to be revisited. Here we address what we have learnt from both trials and how future trials should be designed to investigate CN.

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

Background: Renal cell carcinoma with sarcomatoid dedifferentiation represents a rare histological entity characterized by aggressive behavior, limited efficacy of tyrosine kinase inhibitors or mTOR inhibitors, and poor outcome. The immune checkpoint inhibitor therapy regimen combining ipilimumab with nivolumab represents a new standard of care for this patient population due to a hitherto unprecedented response rate and overall survival. On the other hand, the role of cytoreductive nephrectomy in metastatic renal cell carcinoma, in particular, with sarcomatoid histology, remains controversial. Patient and Methods: In the present case series, we report six patients with locally advanced or synchronous metastatic sarcomatoid renal cell carcinoma and intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk score, five of whom were successfully subjected to cytoreductive nephrectomy. Results: All six patients received the combination regimen of ipilimumab with nivolumab. Five of these patients underwent upfront cytoreductive nephrectomy followed by systemic treatment without any significant delay, with a durable treatment outcome. Notably, two patients with poor prognostic features achieved a long-term major partial response to therapy. We also performed a review of the literature on optimal treatment strategies for patients with sarcomatoid renal cell carcinoma. Conclusion: Herein, we highlight the feasibility of performing cytoreductive nephrectomy in patients with intermediate/poor prognosis metastatic renal cell carcinoma with sarcomatoid dedifferentiation followed by immunotherapy with ipilimumab and nivolumab. To enhance the chances of immunotherapy success, cytoreductive nephrectomy should also be considered for patients presenting with a disease with adverse prognostic parameters.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. During a median follow-up period of 12.0months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P=0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P=0.0613). The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Complementary roles of surgery and systemic treatment in clear cell renal cell carcinoma.

Standard-of-care management of renal cell carcinoma (RCC) indisputably relies on surgery for low-risk localized tumours and systemic treatment for poor-prognosis metastatic disease, but a grey area remains, encompassing high-risk localized tumours and patients with metastatic disease with a good-to-intermediate prognosis. Over the past few years, results of major practice-changing trials for the management of metastatic RCC have completely transformed the therapeutic options for this disease. Treatments targeting vascular endothelial growth factor (VEGF) have been the mainstay of therapy for metastatic RCC in the past decade, but the advent of immune checkpoint inhibitors has revolutionized the therapeutic landscape in the metastatic setting. Results from several pivotal trials have shown a substantial benefit from the combination of VEGF-directed therapy and immune checkpoint inhibition, raising new hopes for the treatment of high-risk localized RCC. The potential of these therapeutics to facilitate the surgical extirpation of the tumour in the neoadjuvant setting or to improve disease-free survival in the adjuvant setting has been investigated. The role of surgery for metastatic RCC has been redefined, with results of large trials bringing into question the paradigm of upfront cytoreductive nephrectomy, inherited from the era of cytokine therapy, when initial extirpation of the primary tumour did show clinical benefits. The potential benefits and risks of deferred surgery for residual primary tumours or metastases after partial response to checkpoint inhibitor treatment are also gaining interest, considering the long-lasting effects of these new drugs, which encourages the complete removal of residual masses.

Efficacy of cabozantinib therapy for brain metastases from renal cell carcinoma

IntroductionWe report two cases of renal cell carcinoma with brain metastases that showed remarkable responses to cabozantinib.Case presentation(Case 1) A 70‐year‐old man with cT3aN0M0 clear cell renal cell carcinoma underwent radical nephrectomy and developed multiple brain metastases 2 months postoperatively. The brain lesions regressed after stereotactic radiotherapy followed by ipilimumab plus nivolumab therapy, but a new brain metastasis that caused hemiplegia developed after 6 months and showed no response to stereotactic radiotherapy. However, complete remission was achieved, and hemiplegia ceased within 2 weeks of cabozantinib therapy. (Case 2) A 63‐year‐old man with cT3aN0M1 clear cell renal cell carcinoma and brain metastases underwent upfront cytoreductive nephrectomy. The brain lesions progressed rapidly 1 month postoperatively. The lesions disappeared 2 weeks after cabozantinib plus nivolumab therapy.ConclusionCabozantinib, alone or in combination with immune checkpoint inhibitors, may be a viable option for clear cell renal cell carcinoma with brain metastases.