Deferred Cytoreductive Nephrectomy Following Presurgical Vascular Endothelial Growth Factor Receptor-targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A Pooled Analysis of Prospective Trial Data.

Cancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting. The aim of this study was to compare outcome in patients treated with presurgical VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI (upfront CN). Pooled data from prospective trials in which a strategy of deferred CN in the absence of disease progression was investigated were compared with a retrospective dataset of upfront CN. Overall survival (OS) in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group. Patients were treated between 2006 and 2016. In the MSKCC intermediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo (95% confidence interval [CI] 25.0-51.0) compared with 22.8 mo (95% CI 17.9-30.6) after upfront CN (hazard ratio 0.72 [95% CI 0.52-0.996], p = 0.047). This study is limited by retrospective comparison of data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort. In MSKCC intermediate-risk patients, a strategy of deferred CN in the absence of progression yields OS, which compares favourably with upfront CN and published trial data from CARMENA. This warrants a formal individual patient data analysis of CARMENA, SURTIME, and single-arm prospective studies to define the role and timing of deferred CN in intermediate-risk patients. In this study, we report outcomes in patients with metastatic renal cell cancer treated with targeted therapy followed by nephrectomy, which compared favourably with nephrectomy followed by targeted therapy and results from published studies.

de Bruijn R ，Wimalasingham A ，Szabados B ，Stewart GD ，Welsh SJ ，Kuusk T ，Blank C ，Haanen J ，Klatte T ，Staehler M ，Powles T ，Bex A ... -  《European Urology Oncology》

Too good for CARMENA: criteria associated with long systemic therapy free intervals post cytoreductive nephrectomy for metastatic clear cell renal cell carcinoma.

Roussel E ，Verbiest A ，Milenkovic U ，Van Cleynenbreugel B ，Van Poppel H ，Joniau S ，Beuselinck B ，Albersen M ... -  《-》

Deferred Cytoreductive Nephrectomy in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma.

The use of cytoreductive nephrectomy (CN) selectively for patients who show a favorable response to upfront systemic therapy may be an approach to select optimal candidates with metastatic renal cell carcinoma (mRCC) who are most likely to benefit. We sought to characterize outcomes of deferred CN (dCN) after upfront sunitinib, outcomes relative to sunitinib alone, and outcomes of CN followed by sunitinib. We used the prospectively maintained International mRCC Database Consortium (IMDC) database to identify patients with newly diagnosed mRCC (2006-2018). Sunitinib alone, upfront CN followed by sunitinib, sunitinib followed by dCN. Outcomes were overall survival (OS) and time to sunitinib treatment failure (TTF). Kaplan-Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias. We evaluated 1541 patients, of whom 651 (42%) received sunitinib alone, 805 (52%) underwent CN followed by sunitinib, and 85 (5.5%) received sunitinib followed by dCN, at a median of 7.8 mo from diagnosis. Median OS periods for patients treated with sunitinib alone, CN followed by sunitinib, and sunitinib followed by dCN were 10, 19, and 46 mo, respectively, while the median TTF values were 4, 8, and 13 mo, respectively. In multivariable regression analyses, sunitinib followed by dCN was significantly associated with improved OS (hazard ratio [HR] = 0.45, 95% confidence interval [CI] 0.33-0.60, p < 0.001) and TTF (HR = 0.62, 95% CI 0.46-0.85, p = 0.003) versus sunitinib alone. Among CN-treated patients, sunitinib followed by dCN was associated with improved OS (HR = 0.52, 95% CI 0.39-0.70, p < 0.001) and TTF (HR = 0.71, 95% CI 0.56-0.90, p = 0.005) compared with upfront CN followed by sunitinib. In various sensitivity analyses, dCN remained significantly associated with improved OS and TTF. Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted. We characterized benchmark survival outcomes for patients with metastatic kidney cancer treated with sunitinib alone, nephrectomy (kidney removal) followed by sunitinib, and sunitinib followed by nephrectomy. Patients who had their nephrectomy after an initial course of sunitinib had prolonged survival.

Bhindi B ，Graham J ，Wells JC ，Bakouny Z ，Donskov F ，Fraccon A ，Pasini F ，Lee JL ，Basappa NS ，Hansen A ，Kollmannsberger CK ，Kanesvaran R ，Yuasa T ，Ernst DS ，Srinivas S ，Rini BI ，Bowman I ，Pal SK ，Choueiri TK ，Heng DYC ... -  《-》

Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma.

The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial. To assess if CN versus no CN is associated with improved overall survival (OS) in patients with mRCC treated in the TT era and beyond, characterize the morbidity of CN, identify prognostic and predictive factors, and evaluate outcomes following treatment sequencing. Medline, EMBASE, and Cochrane databases were searched from inception to June 4, 2018 for English-language clinical trials, cohort studies, and case-control studies evaluating patients with mRCC who underwent and those who did not undergo CN. The primary outcome was OS. Risk of bias was evaluated using the Cochrane Collaborative tools. We identified 63 reports on 56 studies. Risk of bias was considered moderate or serious for 50 studies. CN was associated with improved OS among patients with mRCC in 10 nonrandomized studies, while one randomized trial (CARMENA) found that OS with sunitinib alone was noninferior to that with CN followed by sunitinib. The risk of perioperative mortality and Clavien ≥3 complications ranged from 0% to 10.4% and from 3% to 29.4%, respectively, with no meaningful differences between upfront CN or CN after presurgical systemic therapy (ST). Notably, 12.9-30.4% of patients did not receive ST after CN. Factors most consistently prognostic of decreased OS were progression on presurgical ST, high C-reactive protein, high neutrophil-lymphocyte ratio, poor International Metastatic renal cell carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) risk classification, sarcomatoid dedifferentiation, and poor performance status. At the same time, good performance status and good/intermediate IMDC/MSKCC risk classification were most consistently predictive of OS benefit with CN. In a randomized trial investigating the sequence of CN and ST (SURTIME), an OS trend was observed with CN after a period of ST in patients without progression compared with upfront CN. However, the study was underpowered and results are exploratory. Currently, ST should be prioritized in the management of patients with de novo mRCC who require medical therapy. CN maintains a role in patients with limited metastatic burden amenable to surveillance or metastasectomy, and may potentially be considered in patients with favorable response after initial ST or for symptom's palliation. In the contemporary era, receiving systemic therapy is the priority in metastatic kidney cancer. Nephrectomy still has a role in patients with limited burden of metastases, well-selected patients based on established prognostic and predictive factors, and patients with a favorable response after initial systemic therapy.

Bhindi B ，Abel EJ ，Albiges L ，Bensalah K ，Boorjian SA ，Daneshmand S ，Karam JA ，Mason RJ ，Powles T ，Bex A ... -  《-》

Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.

Bex A ，Mulders P ，Jewett M ，Wagstaff J ，van Thienen JV ，Blank CU ，van Velthoven R ，Del Pilar Laguna M ，Wood L ，van Melick HHE ，Aarts MJ ，Lattouf JB ，Powles T ，de Jong Md PhD IJ ，Rottey S ，Tombal B ，Marreaud S ，Collette S ，Collette L ，Haanen J ... -  《-》