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Cytoreductive Nephrectomy in the Era of Tyrosine Kinase and Immuno-Oncology Checkpoint Inhibitors
Abstract
The role for cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has evolved with advancements in systemic therapy. During the cytokine-based immunotherapy era, CN provided a clear survival benefit and was considered standard of care in management of mRCC. The development of targeted systemic therapy directed at the vascular endothelial growth factor pathway altered the treatment paradigm and accentuated the importance of risk stratification in treatment selection. This article reviews the literature evaluating the benefit of CN during the evolution of systemic therapy and provides clinical recommendations for current utilization of CN in patients with mRCC.
... Worldwide, an estimated 431,300 cases of kidney cancer were newly diagnosed and 179,400 deaths from kidney cancer occurred in 2020 (Siegel et al. 2021). Kidney clear cell carcinoma (KIRC) is the most critical histological subtype of RCC, accounting for about 80-90% of cases (Biles et al. 2020). The prognosis of KIRC is poor, and the disease shows widespread resistance to chemotherapy and radiotherapy (Zhao et al. 2018). ...
Purpose
Kidney clear cell carcinoma (KIRC) has a poor prognosis, high morbidity and mortality rates, and high invasion and metastasis rate, and effective therapeutic targets are lacking. zDHHC3 has been implicated in various cancers, but its specific role in KIRC remains unclear.
Methods
In this study, we performed a pan-cancer analysis, bioinformatics analysis, and cell experiment to detect the role of zDHHC3 in KIRC.
Results
zDHHC3 was significantly down-regulated in KIRC, and that its high expression was associated with favorable patient outcomes. We identified 202 hub genes that were most relevant to high zDHHC3 expression and KIRC, and found that they were involved mainly in ion transport and renal cell carcinoma. Among these hub genes, SLC9A2 was identified as a downstream gene of zDHHC3. zDHHC3 suppression led to decreased expression and S-palmitoylation of SLC9A2, which further inhibited the apoptosis of Caki-2 cells.
Conclusion
Our findings suggest that zDHHC3 plays an important role in KIRC, due partly to its regulation of SLC9A2 S-palmitoylation. The targeting of the zDHHC3–SLC9A2 axis may provide a new option for the clinical treatment of KIRC.
... In the early twentieth century, the immunogenicity of renal cell carcinoma was discovered, leading to the establishment of interferon-alfa (IFN-alfa) and interleu-kin-2 as first-line therapies for metastatic renal cell carcinoma (mRCC) (1)(2)(3). However, the role of cytoreductive nephrectomy (CN) in the treatment of mRCC remains controversial. ...
Purpose
The prognostic impact of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immunotherapy is yet to be determined. The aim of our study is to evaluate the correlation between CN and outcomes in the setting of mRCC treated with immunotherapy.
Methods
We conducted a systematic search of the Science, PubMed, Web of Science, and Cochrane Library databases to identify relevant studies published in English up to December 2022. The results were presented as hazard ratio (HR) with 95% confidence intervals (CIs) for overall survival (OS) was extracted to assess their relevance. The study was registered with PROSPERO (CRD42022383026).
Results
A total of 2397 patients were included in eight studies. The CN group was observed to be correlated with superior OS compared to the No CN group (HR = 0.53, 95% CI 0.39–0.71, p < 0.0001). Subgroup analysis according to the type of immunotherapy, sample size, and treatment line of immune checkpoint inhibitor revealed that CN group had a superior OS in all subgroups.
Conclusion
CN is associated with a better outcome in terms of OS benefit in selected patients with mRCC treated by immunotherapy, but further studies are required to verify the conclusions.
Systematic review registration
https://www.crd.york.ac.uk/prospero/, identifier CRD42022383026.
... However, it is difficult to select Currently, drug treatments for metastatic RCC are diverse and stratified by risk factors using models such as those from the Memorial Sloan-Kettering Cancer Center and the International Metastatic RCC Database Consortium. However, it is difficult to select appropriate cases for study [8][9][10][11][12][13][14][15][16]. In addition, the effectiveness of therapeutic agents has been investigated primarily using nuclear gene information. ...
Simple Summary
We performed mutation analysis of ribonucleic acid sequencing (RNA-seq) and whole mitochondrial genome data from tissues collected from metastatic lesions of a male patient in his 60s with metastatic renal cell carcinoma. We confirmed the common mutation sites of a mitochondrial gene containing the T3394Y, R11,807G, and G15,438R sites. Pathway analysis, using RNA-seq data, confirmed the common mutant pathway between renal cell carcinoma and metastatic adrenal carcinoma as cytokine–cytokine receptor (CCR) interaction. However, no common nuclear gene mutations were identified. The two similar sequences suggest that mtDNA-mutation-driven metastasis to the adrenal gland may affect CCR interactions and cause cancer cells to thrive.
Abstract
This study aimed to clarify whether genetic mutations participate in renal cell carcinoma (RCC) metastasis to the adrenal gland (AG). Our study analyzed whole mitochondrial gene and ribonucleic acid sequencing (RNA-seq) data from a male patient in his 60s with metastatic RCC. We confirmed common mutation sites in the mitochondrial gene and carried out Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using RNA-seq data for RCC and adrenal carcinoma. Furthermore, we confirmed the common mutation sites of mitochondrial genes in which the T3394Y (p.H30Y) site transitioned from histidine (His.; H) to tyrosine (Tyr.; Y) in the NADH dehydrogenase subunit 1 (ND1) gene. The R11,807G (p.T350A) site transitioned from threonine (Thr.; T) to alanine (Ala.; A). Additionally, the G15,438R or A (p.G231D) site transitioned from glycine (Gly.; G) to aspartic acid (Asp.; D) in cytochrome b (CYTB). Furthermore, pathway analysis, using RNA-seq, confirmed the common mutant pathway between RCC and adrenal carcinoma as cytokine–cytokine receptor (CCR) interaction. Confirmation of the original mutation sites suggests that transfer to AG may be related to the CCR interaction. Thus, during metastasis to the AG, mitochondria DNA mutation may represent the initial origin of the metastasis, followed by the likely mutation of the nuclear genes.
... However, in the present study, we found that CN still demonstrated significant OS and CSS advantages, which was in line with many previous findings (12,13). CN provided clear survival benefits and has been considered the standard of care until recently for all patients with mRCC (14). One similar real-world cohort study based on the International Metastatic Renal Cell Carcinoma Database found that patients Frontiers in Surgery | www.frontiersin.org ...
Introduction: The benefit of cytoreductive nephrectomy (CN) for metastatic kidney cancer has been challenged recently. The study aimed to evaluate the prognostic roles of surgical resection of primary tumor site for metastatic kidney cancer under a real-world setting.
Methods: The Surveillance, Epidemiology, and End Results (SEER) database (2010–2015) and the overall survival (OS) and cancer-specific survival (CSS) were evaluated using the Cox proportional hazards regression model. One-to-one matching using the propensity score was used to estimate and compare the survival rates.
Results: The SEER data contain records of 8,932 patients from 2010 to 2015. The data showed that 61.7% of the patients underwent CN while 38.2% did not receive any surgery. The median survival month for a patient without surgery was 4 months and for a patient with surgery was 19 months. The multivariate analysis showed that surgical resection of the primary tumor site was an independent favorable predictor for both OS and CSS (all p < 0.001) in the original and the matching cohort.
Conclusions: In the era of target therapy, CN might still be a vital method to treat metastatic kidney cancer.
... The management of metastatic renal cell carcinoma (mRCC) has undergone a significant shift over the past three decades. The discovery of RCC's immunogenicity led to the establishment of interleukin-2 and interferon-alpha as first-line treatments for mRCC during the 1990s, marking the so called "cytokine era" [3][4][5]. Cytoreductive nephrectomy (CN) refers to the removal of the primary renal tumor in the metastatic setting and met with sporadic success during the 20th century [6,7]. In the early 2000s, CN re-emerged and its combination with cytokine-based immunotherapy became the new standard of care, following the results of two randomized controlled trials (RCTs) [8,9]. ...
317
Background: The role of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy agents remains controversial. We used reconstructed individual patient data (IPD) to compare the long-term survival outcomes of CN combined with targeted therapy vs. targeted therapy alone for mRCC. Methods: We performed a systematic review of the literature using the MEDLINE, Scopus, and Cochrane Library databases (end-of-search date: July 21, 2020). We reconstructed the Kaplan-Meier curves and subsequently recuperated IPD for overall (OS), progression-free (PFS) and cancer-specific survival (CSS) from individual studies. We performed one-stage random-effects frequentist and Bayesian meta-analyses of OS, PFS, and CSS using parametric and non-parametric estimates. We also performed a subgroup analysis focusing on upfront CN and excluding patients with deferred CN. The risk of bias was assessed using the ROBINS-I and RoB2 tools. Results: Fifteen studies fulfilling our inclusion criteria were identified, including fourteen retrospective cohort studies and one randomized controlled trial. No studies were found to be at critical risk of bias. A total of 3,990 patients were included, with 2,234 in the CN group and 1,756 in the non-CN group. Our frequentist meta-analysis showed superior OS (HR = 0.58, 95% CI: 0.54-0.62, p<0.0001) and CSS (HR = 0.63, 95% CI: 0.53-0.75, p < 0.0001) in favor of CN. No clinically meaningful differences were observed in the PFS between the two groups (HR = 0.90, 95% CI: 0.80-1.02, p=0.09). The OS benefit was also observed in the upfront CN subgroup (HR = 0.70, 95% CI 0.63-0.78, p<0.001). Similar results were obtained with non-parametric frequentist and Bayesian approaches (Table). Conclusions: The combination of CN and targeted therapy for mRCC is associated with superior long-term survival outcomes compared with targeted therapy alone. Careful patient selection based on prognostic factors is required to achieve optimal outcomes. [Table: see text]
... The management of metastatic renal cell carcinoma (mRCC) has undergone a significant shift over the past three decades. The discovery of RCC's immunogenicity led to the establishment of interleukin-2 and interferon-alpha as first-line treatments for mRCC during the 1990s, marking the so called "cytokine era" [3][4][5]. Cytoreductive nephrectomy (CN) refers to the removal of the primary renal tumor in the metastatic setting and met with sporadic success during the 20th century [6,7]. In the early 2000s, CN re-emerged and its combination with cytokine-based immunotherapy became the new standard of care, following the results of two randomized controlled trials (RCTs) [8,9]. ...
Simple Summary
Cytoreductive nephrectomy (CN) refers to the removal of the primary renal tumor in the setting of metastatic renal cell carcinoma. In the past, the combination of CN with cytokine-based immunotherapy was considered the standard of care. However, CN’s role during the targeted treatment era remains controversial. We attempted to address this issue by performing a systematic review and meta-analysis of the literature. We synthesized data from 15 studies comparing CN and targeted therapy to targeted therapy alone. Our results show that CN combined with targeted therapy was associated with increased survival compared to targeted therapy only. Careful patient selection is required to take full advantage of any survival benefit that CN may offer. Future research endeavors should focus on developing appropriate prognostic models to guide appropriate patient selection for CN.
Abstract
The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains controversial during the targeted therapy era. To reconcile the current literature, we analyzed the reported survival data at the individual patient level and compared the long-term survival outcomes of CN combined with targeted therapy vs. targeted therapy alone in patients with mRCC. We performed a systematic review of the literature using the MEDLINE, Scopus, and Cochrane Library databases (end-of-search date: 21 July 2020). We recuperated individual patient data from the Kaplan–Meier curves for overall (OS), progression-free (PFS), and cancer-specific survival (CSS) from each study. We subsequently performed one-stage frequentist and Bayesian random-effects meta-analyses using both Cox proportional hazards and restricted mean survival time (RMST) models. Two-stage random-effects meta-analyses were also performed as sensitivity analyses. A subgroup analysis was also performed to determine the effect of CN timing. Fifteen studies fulfilling our inclusion criteria were identified, including fourteen retrospective cohort studies and one randomized controlled trial. In the one-stage frequentist meta-analysis, the CN group had superior OS (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.54–0.62, p < 0.0001) and CSS (HR: 0.63, 95% CI: 0.53–0.75, p < 0.0001). No meaningful clinical difference was observed in PFS (HR: 0.90, 95% CI: 0.80–1.02, p = 0.09). One-stage Bayesian meta-analysis also revealed superior OS (HR: 0.59, 95% credibility interval [CrI]: 0.55–0.63) and CSS (HR: 0.63, 95% CrI: 0.53–0.75) in the CN group, while no meaningful clinical difference was detected in PFS (HR: 0.91, 95% CrI: 0.80–1.02). Similar results were obtained with the RMST models. The OS benefit was also noted in the two-stage meta-analyses models, and in the subgroup of patients who received upfront CN. The combination of CN and targeted therapy for mRCC may lead to superior long-term survival outcomes compared to targeted therapy alone. Careful patient selection based on prognostic factors is required to optimize outcomes.
Introduction:
Despite modern advances in surgical and perioperative technologies, management of renal cell carcinoma (RCC) with tumor thrombus (TT) is a morbid procedure that necessitates careful patient selection. It is not known whether established prognostic models for metastatic RCC are suitable prognostic tools for more immediate perioperative outcomes in patients with RCC with TT. We evaluated if established risk models for cytoreductive nephrectomy, as a potential extension of their purpose-built use, are associated with immediate perioperative outcomes in patients undergoing nephrectomy and tumor thrombectomy.
Methods:
Perioperative outcomes of patients who underwent radical nephrectomy and tumor thrombectomy for RCC were compared to presences of established predictors of long-term outcomes from prior risk models individually and as stratified by risk grouping (International Metastatic Renal-Cell Carcinoma Database Consortium [IMDC], Memorial Sloan Kettering Cancer Center [MSKCC], M.D. Anderson Cancer Center [MDACC], and Moffitt Cancer Center [MCC]). Wilcoxon rank-sum test or the Kruskal-Wallis test compared continuous variables and the chi-square test or Fisher's exact test compared categorical variables.
Results:
Fifty-five patients were analyzed with 17 (30.9%) being cytoreductive. Eighteen (32.7%) patients had a level III or higher TT. Individually, preoperative variables were inconsistently associated with perioperative outcomes. Poorer risk patients per the IMDC model had more major postoperative complications (Clavien-Dindo grade≥3, P = 0.008). For the MSKCC model, poorer risk patients had increased intraoperative estimated blood loss (EBL), longer length of stay (LOS), more major postoperative complications, and more likely to discharge to a rehabilitation facility (P < 0.05). Less favorable risk patients per MDACC model had increased LOS (P = 0.038). Poorer risk patients per the MCC model had increased EBL, LOS, major postoperative complications, and 30-day hospital readmissions (P < 0.05).
Conclusion:
Overall, cytoreductive risks models were heterogeneously associated with perioperative outcomes in patients undergoing nephrectomy and tumor thrombectomy. Of available models, the MCC model is associated with more perioperative outcomes including EBL, LOS, major postoperative complications, and readmissions within 30 days when compared to the IMDC, MSKCC, and MDACC models.
Purpose
Sarcomatoid dedifferentiation in renal cell carcinoma (RCC) represents an aggressive histology where degree of sarcomatoid histology (SH) may impact prognosis for cM0 and cM1 patients. We aimed to evaluate the association of percentage of SH with survival.
Materials and methods
Patients ≥18 years old diagnosed with RCC with any degree of SH after nephrectomy were included (2005–2020) from a single-center. Associations of degree of SH and cM stage with overall survival (OS) and recurrence-free survival (RFS) were evaluated by Kaplan-Meier curves and Cox proportional hazards regression.
Results
One hundred twenty-eight patients were included with 80 (62.5%) cM0 and 48 (37.5%) cM1. cM1 patients were more likely to be male with higher clinical T stage (P = 0.001) than cM0, but a similar proportion had ≥20% SH (47.9% vs. 42.5%, P = 0.55). With median 19.4 months follow-up, SH was associated with worse OS per 10% increase (hazard ratio [HR] 1.12 [95% confidence interval {CI} 1.03–1.23], P = 0.009) and a ≥20% cutoff (HR 2.87 [95% CI 1.27–6.47], P = 0.01). Patients with cM0 disease and <20% SH had better 2-year OS (81.4%) compared to cM0 and ≥20% SH (44.8%) or cM1 patients who received nephrectomy (54.8%). Tumor size was also an independent predictor. Sites of distant metastasis and lines of therapy were similar for metachronous and synchronous patients. SH stratified 2-year RFS (cM0: 70.2% for <20% SH vs. 32.1% for ≥20% SH).
Conclusions
SH in RCC is independently associated with OS and RFS. Patients who are cM0 with any SH may be candidates for adjuvant immunotherapy while those with ≥20% SH likely carry micrometastatic disease and should receive closer surveillance.
Purpose
The best protocol of cytoreductive nephrectomy (CN) and systemic therapy (ST) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear. We sought to evaluate overall survival (OS) in patients with mRCC treated with ST with or without CN.
Methods
We collected data from the National Health Insurance Service database. We excluded 2 years of washout period, 2 years of follow-up period, other cancer diagnoses within 2 years, and ≥4 months interval between ST and CN. The patients were divided into two groups according to whether CN was performed. Kaplan–Meier, propensity score matching, Cox regression model, and incremental survival analyses were conducted. Additionally, we performed subgroup analysis according to whether cytokine therapy or targeted therapy was used as first-line ST.
Results
Of 6478 patients, 1707 (26.4%) underwent CN. The CN group showed significantly better OS than the no CN group (p < 0.001). In the cytokine therapy subgroup, patients who underwent CN had significantly higher OS than those who did not (p < 0.001). In the targeted therapy subgroup, no significant difference was found (p = 0.867). In multivariate analysis, CN was associated with better OS in the total cohort (hazard ratio 0.819, p < 0.001). The incremental OS benefit of CN ranged from +0.98 in patients who survived for <24 months to +2.13 in those who survived during all periods.
Conclusion
About a quarter patients with mRCC from a nationwide database were treated with CN and ST. CN was beneficial in specific patients with mRCC. Patient selection is crucial for obtaining the benefits of CN.
Renal cell carcinoma (RCC) accounts for most renal malignancies. This article, the last in a three-part series, presents treatment options for RCC using the American Joint Committee on Cancer Tumor, Node, and Metastasis staging system as a framework, as well as nursing-care options for patients undergoing partial or radical nephrectomy.
Introduction
: Renal cell carcinoma is no longer considered a monolithic disease, but a group of different entities exhibiting unique molecular alterations requiring a tailored systemic therapy approach. One of the remaining challenges is the identification of the best candidate for a particular therapeutic regimen.
Areas covered
: The current literature regarding the recent advances and treatment options in systemic therapy for metastatic RCC, and issues pertaining the available biomarkers tested to date for a correct treatment stratification.
Expert opinion
: Underlying biology of RCC will still drive the development of new treatment agents/combinations that will be tested in earlier stages of the disease, and probably prove to have a role in the neoadjuvant/adjuvant settings. The correct characterization of the tumor microenvironment through transcriptomic analysis should help to overcome the issues related to tumor heterogeneity. Preclinical ex-vivo models will enlarge our current knowledge regarding the potential immune escape mechanisms exhibited by RCC, and facilitate a better monitoring of the response to therapy. New tracers, image modalities, and tests aimed at detecting and analyzing tumor circulating cells will improve our clinical performance through a better identification of the metastatic site locations and their variable histologic patterns, and ultimately their behavior in response to treatment.
Background:
In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited.
Objective:
To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies.
Design, setting, and participants:
Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo.
Intervention:
All patients received first-line IO combination therapies.
Outcome measurements and statistical analysis:
First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors.
Results and limitations:
In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] -8% to 22%, p = 0.4), TTF was 14.3 versus 10.2 mo (p = 0.2), TNT was 19.7 versus 17.9 mo (p = 0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46-1.12, p = 0.14), 0.65 (95% CI 0.38-1.11, p = 0.11), and 1.74 (95% CI 0.82-3.68, p = 0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3-57%, p = 0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p = 0.4; n = 55). Limitations include the study's retrospective design and sample size.
Conclusions:
There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially.
Patient summary:
There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.
Background:
In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.
Methods:
In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.
Findings:
Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.
Interpretation:
The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.
Funding:
Bristol-Myers Squibb and ONO Pharmaceutical.
The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgery-related adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24 h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2 wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD ≥3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay.
Patient summary
Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery.
Recent randomised trials have demonstrated a survival benefit for a front-line ipilimu-mab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies. Patient summary: Pembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naïve). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.
Background:
There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC). This has been studied predominantly in clear-cell RCC, with more limited data on the role of CN in patients with papillary histology.
Objective:
To determine the benefit of CN in synchronous metastatic papillary RCC.
Design, setting, and participants:
Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) database, a retrospective analysis was performed for patients with papillary mRCC treated with or without CN.
Outcome measurements and statistical analysis:
Median overall survival (OS) and progression-free survival (PFS) were determined for both patient groups. Cox regression analysis was performed to control for imbalances in individual IMDC risk factors.
Results and limitations:
In total, 647 patients with papillary mRCC were identified, of whom 353 had synchronous metastatic disease. Of these, 109 patients were treated with CN and 244 were not. The median follow-up was 57.1mo (95% confidence interval [CI] 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2mo (95% CI 12.0-16.1). Median OS for patients with CN was 16.3mo, compared to 8.6mo (p<0.0001) in the no-CN group. When adjusted for individual IMDC risk factors, the hazard ratio (HR) of death for CN was 0.62 (95% CI 0.45-0.85; p=0.0031). Limitations include the retrospective nature of the analysis.
Conclusions:
The use of CN in patients with mRCC and papillary histology appears to be associated with better survival compared to no CN after adjustment for risk criteria. Selection of appropriate candidates for CN is crucial. A clinical trial in this rare population may not be possible.
Patient summary:
In a population of patients with advanced papillary kidney cancer, we found that surgical removal of the primary kidney tumor was associated with better overall survival.
Background
The rising incidence of renal cell carcinoma (RCC) since the 1980s has been accompanied by stage migration toward early-stage (stage I) cancers. Stage migration drove an apparent increase in survival for RCC since the 1980s, but it is unclear whether it remains a contributor more recently.
Objective
To determine whether clinical stage migration has persisted and the relative impact of stage migration versus improvements in treatment on survival for RCC.
Design, setting, and participants
An epidemiologic assessment of stage migration and survival for 262 597 patients at diagnosis of RCC (2004–2015) across >1500 facilities in the National Cancer Database.
Outcome measurements and statistical analysis
Proportion of patients over time was assessed by clinical stage at diagnosis via Cochran-Armitage chi-square tests and linear regression. Mortality data were assessed with the Kaplan-Meier method for 5-yr overall survival, Cox proportional hazards regression, and propensity score matching to differentiate the impact of treatment including systemic therapy from stage migration.
Results and limitations
Greater diagnosis of clinical stage I disease (70%; p < 0.001) was observed, with decreased diagnosis of stage III (8%; p < 0.001) and stage IV (11%; p < 0.001) up to 2007 followed by stabilization through 2015. Tumor size continues to decrease for localized tumors (mean–0.22 cm stage I and–1.24 cm stage II, 2004–2015). Histology demonstrated significant associations with stage. Five-year overall survival improved (67.9% [2004] to 72.3% [2010]) with gains in advanced RCC but not localized tumors. Models confirmed improved survival in recent years for stage IV patients. Systemic therapy was associated with improved survival (hazard ratio 0.811 [0.786–0.837], p < 0.001). National Cancer Database limitations apply.
Conclusions
The proportion of patients presenting with stage I RCC has stabilized (70%), suggesting that stage migration may have ended. Localized tumors are detected with decreasing size, while advanced cancers have remained stable. Only 11% of patients now present with distant metastatic disease, but 5-yr overall survival is improving in recent years due to improved treatments rather than stage migration.
Patient summary
In this study, we found that stage migration toward early-stage cancers has ended for renal cell carcinoma (RCC). However, improved treatment for advanced RCC appears to be responsible for improved survival in recent years.
Cytoreductive nephrectomy (CN) has been the standard of care in patients with metastatic clear-cell renal cancer who present with the tumour in place. The CARMENA trial compared systemic therapy alone with CN followed by systemic therapy. This article outlines the new guidelines based on these data.
Patient summary:
The CARMENA trial demonstrates that immediate cytoreductive nephrectomy should no longer be considered the standard of care in patients diagnosed with intermediate and poor risk metastatic renal cell carcinoma when medical treatment is required. However, the psychological burden poor risk patients experience hearing that removal of their primary tumour will not be beneficial, should be carefully considered.
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases. A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.
Background
Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.
Methods
We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level,0.04), objective response rate (alpha level,0.001), and progression-free survival (alpha level,0.009) among patients with intermediate or poor prognostic risk.
Results
A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups.
Conclusions
Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749.)
Despite advances in systemic therapy for metastatic renal cell carcinoma, durable responses remain rare and surgical management remains a mainstay of treatment for many patients with metastatic disease. Management of the primary tumor in metastatic patients can occur as 1) palliative nephrectomy for symptomatic patients in whom cure is not achievable, 2) cytoreductive nephrectomy before systemic therapy, or 3) consolidative nephrectomy after systemic therapy. Palliative nephrectomy is rarely performed in centers where angioembolization is available. The evidence for cytoreductive nephrectomy is based on randomized trials in the cytokine era and retrospective studies in the more recent targeted therapy era. Consolidative nephrectomy is utilized after systemic therapy for intermediate- and poor-risk patients or in patients with potentially unresectable disease based on retrospective evidence. Resection of metastatic lesions, or metastasectomy, is utilized in select patients, with efficacy predicated on the organs involved and the extent of resection that is achievable, based on retrospective data. Herein, the evidence for surgical management of both the primary tumor and metastatic lesions in patients with metastatic renal cell carcinoma is reviewed.
The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.
Introduction:
Current treatment paradigms for metastatic renal cell carcinoma (mRCC) invoke a combination of surgical and systemic therapies. We sought to quantify trends in mortality and performance of lymphadenectomy, as well as impact on survival for patients with mRCC.
Methods:
The Surveillance, Epidemiology, and End Results registry (SEER) (1988-2011) identified patients with mRCC. Kaplan-Meier curves and Cox proportional hazards models with competing risks regression were employed to assess survival.
Results:
15 060 patients with mRCC were identified, with 6316 (41.9%) undergoing cytoreductive nephrectomy. Mean number of lymph nodes removed was 6.2, with mean 3.3 positive nodes among 1018 (43.9%) patients with positive nodes. Median overall survival (OS) increased from seven to 11 months (1999-2010), and finding a positive node decreased median cancer survival from 22 to nine months. Cancer-specific survival (CSS) showed significant decreases in mortality after 2005 (hazard ratio [HR] 0.71 [0.60-0.83] comparing 2010 to 1990). Lymphadenectomy was associated with decreased OS (HR 1.10 [1.03-1.16]; p=0.002) due to decreased CSS (HR 1.10 [1.04-1.17]; p<0.001) without increase in other-cause mortality (HR 0.94 [0.79-1.11]; p=0.455). However, more extensive lymphadenectomy ≥3 lymph nodes removed did not significantly impact OS or CSS. Number of positive lymph nodes was associated with decreased CSS.
Conclusions:
mRCC continues to carry a poor prognosis, but current treatment paradigms have led to modest improvements in OS and CSS in recent years. Lymphadenectomy was found to play a prognostic rather than therapeutic role in the management of mRCC. The performance of lymphadenectomy should be limited based on clinical judgment and better incorporated into randomized trials of new systemic therapies to identify scenarios where implementation may improve survival.
Background:
A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance.
Methods:
In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing.
Findings:
Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma.
Interpretation:
A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach.
Funding:
None.
Purpose:
The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) has become unclear since the introduction of targeted therapies (TT). We sought to evaluate contemporary utilization rates of CN and to examine the survival benefit of CN compared with non-CN patients treated with TT.
Methods:
We used the National Cancer Data Base to identify patients with clinical mRCC treated with TT between 2006 and 2013. The intervention of interest was CN. Multivariable logistic regression predicting receipt of CN was performed. Overall survival (OS) was examined using Cox regression models and incremental survival analyses were performed. Sensitivity analyses using propensity scores were conducted.
Results:
Of 15,390 patients treated with TT, 5,374 (35%) underwent CN between 2006 and 2013. Patients who were younger, privately insured, treated at an academic center, and had lower tumor stage and cN0 disease were more likely to undergo CN. The median OS of CN versus non-CN patients was 17.1 (95% CI, 16.3 to 18.0 months) versus 7.7 months (95% CI, 7.4 to 7.9 months; P < .001). In sensitivity analyses using propensity scores adjustment in addition to other available covariates, CN patients had a lower risk of any death (hazard ratio, 0.45; 95% CI, 0.40 to 0.50; P < .001). The survival benefit of CN was +0.7 and +3.6 months in patients who survived ≤ 6 and ≤ 24 months, respectively, versus no CN.
Conclusion:
CN is performed in three of 10 patients with mRCC who are receiving TT. Several patient and sociodemographic characteristics were associated with receipt of CN. When feasible, CN may offer an OS benefit when combined with TT.
We report a patient with metastatic clear-cell renal cell carcinoma (mRCC) who presented with primary tumor in situ in the left kidney and metastases to bone, liver, lungs, and brain. After over 5 years of sunitinib therapy and subsequent cytoreductive left nephrectomy, the patient achieved radiographic complete response (CR) and had pathologic CR in the nephrectomy specimen. Durable clinical and pathological CRs are possible with targeted agents, even with primary tumor in situ and widely disseminated metastases. Ongoing research will define the optimal duration of systemic therapy in exceptional responders and identify the molecular determinants of response and resistance.
Objective
To evaluate whether poor nutrition is associated with mortality in patients undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC).
Patients and Methods
A multi‐institutional review of prospective databases identified 246 patients meeting inclusion criteria who underwent CN for mRCC from 1993 to 2012. Nutritional markers evaluated were: body mass index <18.5 kg/m², serum albumin <3.5 g/dL, or preoperative weight loss of ≥5% of body weight. Primary outcomes were overall (OS) and disease‐specific survival (DSS). Secondary outcome was ‘early mortality’ defined as death at ≤6 months of surgery. Survival curves were estimated using the Kaplan–Meier product‐limit method and multivariate analysis using logistic regression was used to test associations between nutritional markers and survival outcomes.
Results
In all, 119 patients (median follow‐up 17 months) were categorised as having any abnormal nutrition parameter (48%). Hypoalbuminaemia was the only independent predictor of OS and DSS (OS: median 8 vs 23 months, P < 0.001; DSS: 11 vs 33 months, P < 0.001). On multivariate analysis, hypoalbuminaemia remained a significant predictor of death for both overall [hazard ratio (HR) 2, 95% confidence interval (CI) 1.4–2.8; P < 0.001) and disease‐specific mortality (HR 2.2, 95% CI 1.4–3.3; P < 0.001). Hypoalbuminaemia was also associated with early mortality (overall: P < 0.001 and disease specific: P = 0.002).
Conclusion
Patients with mRCC and hypoalbuminaemia undergoing CN have decreased OS and CSS, and increased risk of all‐cause and disease‐specific early mortality. As such, serum albumin may help risk stratify patients selected as candidates for CN. Furthermore, future work should evaluate whether nutritional depletion is a modifiable risk factor.
Background:
The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.
Objective:
To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.
Design, setting, and participants:
Retrospective data from patients with synchronous mRCC (n=1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.
Outcome measurements and statistical analysis:
OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.
Results and limitations:
Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p<0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52-0.69; p<0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.
Conclusions:
CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.
Patient summary:
We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.
Purpose:
If immune cells are involved in tumor surveillance and have a prognostic impact in most primary tumors, little is known about their significance in metastases. Because patients' survival is heterogeneous, even at metastatic stages, we hypothesized that immune cells may be involved in the control of metastases. We therefore characterized the tumor immune microenvironment and its prognostic value in colorectal and renal cell carcinoma (RCC) metastases, and compared it to primary tumors.
Experimental design:
We analyzed by immunohistochemistry (n = 192) and qPCR (n = 32) the immune environments of colorectal carcinoma and RCC lung metastases.
Results:
Metastases from colorectal carcinoma and RCC have different immune infiltrates. Higher densities of DC-LAMP(+) mature dendritic cells (P < 0.0001) and lower densities of NKp46(+) NK cells (P < 0.0001) were observed in colorectal carcinoma as compared to RCC metastases, whereas densities of T cells were similar. High densities of CD8(+) and DC-LAMP(+) cells correlated with longer overall survival (OS) in colorectal carcinoma (P = 0.008) and shorter OS in RCC (P < 0.0001). High NK-cell densities were associated with improved survival in RCC (P = 0.002) but not in colorectal carcinoma. Densities of immune cells correlated significantly from primary to relapsing metastases for the same patient. A TH1 orientation was found in colorectal carcinoma metastases, whereas a heterogeneous immune gene expression was found in RCC metastases.
Conclusions:
Our results show a major prognostic value of the immune pattern (CD8(+)/DC-LAMP(+) cell densities) in colorectal carcinoma and RCC, reproducible from primary to metastatic tumors, although with opposite clinical impacts, and highlight the role of the tumor cell in shaping its immune environment.
Activation of the transcription factor NFκB in peripheral blood T cells from patients with renal cell carcinoma (RCC) is compromised. This impaired signaling function results from a failure of RelA and c-Rel to translocate to the nucleus though normal levels of Rel proteins are present in the cytoplasm. We demonstrate here in a subset of RCC patients that the defect in NFκB activation is attributable to the absence of phosphorylation and degradation of the inhibitor IκB. In patient T cells there was no stimulus dependent decrease in the cytoplasmic level of IκB. Coimmunoprecipitation studies showed that RelA was in complex with IκB and was not released after stimulation. Moreover, the phosphorylated form of IκB detected in normal T cells after activation is absent in patient T cells. Additional experiments showed that soluble products from RCCs (RCC-S) can reproduce the same phenotype in T cells from healthy individuals. Supernatant fluid from cultured explants of RCC, but not normal kidney, inhibited the stimulus dependent nuclear translocation of NFκB without altering the cytoplasmic levels of RelA, c-Rel, and NFκB1. Phosphorylation and degradation of IκB was also blocked by RCC-S. The mechanistic similarities between patient-derived T cells and normal T cells cultured with RCC-S suggest that the tumor-derived products may be the primary mediators of impaired T-cell function in this tumor system.
© 1998 by The American Society of Hematology.
Background: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. Methods: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. Findings: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57–0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76–1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3–4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. Interpretation: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. Funding: F Hoffmann–La Roche Ltd and Genentech Inc.
Background
In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.
Methods
We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)–positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.
Results
A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1–positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1–positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.
Conclusions
Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.)
Background
The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.
Methods
In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.
Results
After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab–axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab–axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab–axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab–axitinib group and in 70.6% in the sunitinib group.
Conclusions
Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.)
Importance
In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.
Objective
To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.
Design, Setting, and Participants
This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied.
Interventions
Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy.
Main Outcomes and Measures
Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points.
Results
The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%).
Conclusions and Relevance
Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib.
Trial Registration
ClinicalTrials.gov identifier: NCT01099423.
Despite the evolution of systemic therapy from the immunotherapy to targeted therapy eras, surgical management remains a mainstay of treatment of patients with locally advanced, lymph node-positive, and distant metastatic renal cell carcinoma. Balancing patient and disease characteristics with the potential morbidity of surgery has gained increasing attention to better define the role of cytoreductive nephrectomy and lymphadenectomy. In this review, we critically evaluate the literature for the potential therapeutic role of cytoreductive nephrectomy and lymphadenectomy in advanced kidney cancer, highlighting current evidence, limitations, and best-management practices. Although retrospective data supported a similar survival benefit for cytoreductive nephrectomy in the targeted therapy era as it did for the initial immunotherapy era (1992 to 2006), level 1 evidence from the randomized Clinical Trial to Assess the Importance of Nephrectomy (CARMENA) demonstrated no benefit for intermediate- and poor-risk patients in the setting of sunitinib therapy. Level 1 evidence among a favorable-risk subset is still awaited from the trial Targeted Therapy With or Without Nephrectomy in Metastatic Renal Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery (TARIBO). Another trial, Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME), has compared upfront cytoreductive nephrectomy prior to targeted therapy with the initial initiation of targeted therapy followed by deferred cytoreductive nephrectomy. Lymphadenectomy is yet another controversial but less well-defined management option for patients with kidney cancer. The role of lymphadenectomy has been studied in both the localized and advanced settings over the past few decades, with a strong suggestion of no therapeutic benefit for patients with cT1-2N0M0 and cM1 disease, and with uncertain benefit in patients with high-risk disease (ie, locally advanced or cN1M0), leading to weak statements among clinical guidelines.
Context
Systemic therapy for metastatic clear cell renal cell carcinoma (mccRCC) has greatly evolved over the last 15 yr. More recently, combination strategies involving contemporary immunotherapy have emerged as key opportunities to further shift the treatment landscape.
Objective
To review the evidence regarding the efficacy and safety of standard therapeutic options in mccRCC as well as combination immunotherapy options on the horizon.
Evidence acquisition
PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to February 2018 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed.
Evidence synthesis
Twenty-six studies were included regarding therapies for metastatic RCC including vascular endothelial growth factor (VEGF)-directed therapy (n = 9), mTOR inhibitors (n = 2), cytokines (n = 3), vaccines (n = 3), and immune checkpoint inhibitors (ICIs, n = 9). VEGF tyrosine kinase inhibitor monotherapy had been the standard therapy, and its use is evolving in the front-line setting with ICIs; cabozantinib provides superior progression-free survival versus sunitinib in intermediate- and poor-risk patients, by International Metastatic RCC Database Consortium criteria. The mTOR therapy is largely inferior to VEGF-directed therapy, although it has a role in combination strategies. Cytokines have largely been replaced in current practice throughout most regions, and vaccines have failed to show improved survival in phase III studies to date. ICIs have now become standard care in untreated patients with intermediate and poor risks, given overall survival benefit seen with CheckMate-214 study; survival data from IMmotion 151 are not yet mature. Several ongoing phase III combination trials, with promising early-phase data, are due to be read out.
Conclusions
The treatment landscape for mccRCC has evolved since the introduction of VEGF inhibitors. Combination therapies involving checkpoint inhibitors could be the next standard of care.
Patient summary
With the expanding role of immune checkpoint inhibitors in metastatic renal cell carcinoma, the treatment paradigm has shifted to include combination therapy in the untreated setting. As the field advances, the bar has been raised in evaluating ongoing combination strategies.
Background
Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies.
Methods
In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival.
Results
A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy–sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy–sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group.
Conclusions
Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique–Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033.)
Background:
The benefit of cytoreductive nephrectomy (CNT) for cancer-specific mortality (CSM)-free survival is unclear in contemporary metastatic non-clear cell renal cell carcinoma (non-ccmRCC) patients.
Objective:
To assess the role of CNT in non-ccmRCC patients.
Design, setting, and participants:
Within Surveillance, Epidemiology, and End Results registry (2001-2014), we identified patients with non-ccmRCC.
Intervention:
CNT versus no CNT in non-ccmRCC patients.
Outcome measurements and statistical analysis:
Multivariable logistic regression, cumulative incidence, competing-risks regression models, incremental survival benefit (ISB), conditional survival, and landmark analyses were performed. Sensitivity analyses focused on histological subtypes and most contemporary patients (2010-2014).
Results and limitations:
Of 851 patients with non-ccmRCC, 67.6% underwent CNT. In multivariable logistic regression, year of diagnosis in contemporary (p<0.001) and intermediate (p=0.008) tertiles, as well as age ≥75 yr (p<0.001) yielded lower CNT rates. Cumulative incidence showed 2-yr CSM of 52.6% versus 77.7%, respectively, after CNT versus no CNT. CSM after CNT versus no CNT was invariably lower in all histologic subtypes and in contemporary patients. Multivariable competing-risks regression models predicting CSM favored CNT (hazard ratio [HR]: 0.38, confidence interval: 0.30-0.47, p<0.001) in all patients and in all subgroups defined by histologic subtypes (HR: 0.14-0.43, all p≤0.02), as well as in contemporary patients (HR: 0.32, p<0.001). The ISB analyses yielded statistically significant and clinically meaningful CSM-free survival benefit of +3 mo after CNT versus no CNT in individuals with observed CSM-free survival ≤24 mo. The 2-yr CSM-free survival increased from baseline of 46.1% versus 19.4% (Δ=26.7%, p<0.001) to 70.3% versus 54.4% (Δ=15.9%, p=0.005) after CNT versus no CNT, in patients that survived 12 mo, respectively. Landmark analyses rejected bias favoring CNT. Data were retrospective.
Conclusions:
CSM is lower after CNT for non-ccmRCC in all histologic subtypes and in contemporary patients except for unproven ISB in collecting duct patients. This observation should encourage greater CNT consideration in non-ccmRCC.
Patient summary:
Cytoreductive nephrectomy appears to improve survival in metastatic non-clear cell renal cell carcinoma, but it is used infrequently.
Purpose:
Two randomized trials in the cytokine era showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC), increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib, in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy. Therefore it is unknown if similar survival benefit with targeted agents could be achieved without CN. We hypothesize that in these patients CN could increase overall survival (OS) in comparison to targeted therapy without CN. We also will investigate mechanisms of primary and secondary resistance to TKIs in patients with mRCC and identify prognostic or predictive biomarkers.
Methods:
This is a randomized, open-label, controlled, multicenter phase 3 study comparing sunitinib or pazopanib vs CN followed by sunitinib or pazopanib as first-line therapy for patients with mRCC who have not received surgery and prior systemic treatment for metastatic disease. We will identify 270 patients eligible for randomization. The planned treatment duration per patient will be until progressive disease is observed. Secondary endpoints are the evaluation of progression-free survival (PFS) and response rate and the assessment of the safety profile. Exploratory objectives include the evaluation of circulating tumor cells and circulating tumor DNA and correlation with response/resistance to treatment.
Results:
The study is enrolling patients.
Conclusions:
The use of CN in addition to targeted therapy in patients with renal cell carcinoma with synchronous metastases could lead to a significant improvement in OS and PFS.
In the pre-targeted therapy era, palliative cytoreductive nephrectomy combined with cytokine immunotherapy was the standard treatment protocol for the management of metastatic renal cell carcinoma. The introduction of targeted therapies has improved response rates, median survival and overall prognosis when compared to immunotherapy. The role of cytoreductive nephrectomy in providing an independent survival advantage when used alongside immunotherapy has been demonstrated by two randomised controlled trials. However, with the new shift in improved treatment outcomes from cytokine immunotherapy to targeted therapies, the continuing role of cytoreductive nephrectomy as a viable surgical treatment modality remains controversial. This article is protected by copyright. All rights reserved.
PURPOSETo determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma.PATIENTS AND METHODS
Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients.RESULTSThe overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesi...
Kidney cancers have been extensively studied, and insights from an increased understanding of tumor biology have led to increases in survival rates. Therapies aimed at tumor signaling pathways and immunotherapies have improved the outlook for patients with renal cancer.
The incidence of renal cell carcinoma is increasing, with up to one-third of patients presenting with metastatic disease. Combination therapy is used to prolong survival in patients with metastatic renal cell carcinoma, which carries a poor prognosis. Although two pivotal phase 3 trials have demonstrated the efficacy of immunotherapy after cytoreductive nephrectomy for metastatic disease, for now, targeted therapy has replaced immunotherapy as the preferred systemic treatment in these patients. Two ongoing phase 3 trials are evaluating the role of cytoreductive nephrectomy prior to targeted therapy. Proper patient selection is paramount in achieving successful outcomes. © 2016, Millennium Medical Publishing, Inc. All rights reserved.
Objectives:
To evaluate the effect of cytoreductive nephrectomy (CN) on overall survival (OS) in primary metastatic renal cell carcinoma (mRCC) patients treated with first-line sunitinib.
Methods:
Patients with primary mRCC treated with first-line sunitinib were selected from a Dutch population-based registry. A propensity score was calculated reflecting the probability of a patient undergoing CN prior to sunitinib using a set of known covariates, such as the MSKCC and IMDC risk factors. After propensity score matching, differences in OS were analysed using the Kaplan-Meier method and a multivariable Cox proportional hazards model was used to evaluate the effect of CN on OS.
Results:
227 patients met the selection criteria; 74 patients (33%) underwent CN prior to sunitinib. In the matched population, median OS of patients who underwent CN was 17.9 months compared to 8.8 months for patients treated with sunitinib only. Multivariable analysis showed that CN was an independent predictor of OS (HR 0.61; 95%CI: 0.41-0.92). A subgroup analysis of patients with a time to targeted therapy <1 year showed a median OS of 12.7 months for patients treated with CN compared to 8.0 months for patients treated with sunitinib only. The corresponding HR was 0.67 (95%CI: 0.46-0.98).
Conclusions:
This study suggests that CN may be effective. However, the benefit was modest when correcting for time from diagnosis to sunitinib. One important limitation is the use of a registry (with retrospectively collected data), which made it impossible to correct for unmeasured characteristics that could be associated with treatment choices or survival.
Cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) (resection of the primary tumour for debulking purposes) was considered to be an important part of oncological treatment when used with cytokines, and was associated with an overall survival (OS) benefit. However, the role of CN in the targeted therapy era is not well defined. We conduct a systematic review and meta-analysis to determine the prognostic role of CN performed during the course of advanced disease in patients with mRCC treated with molecular agents.
To describe the dissemination of targeted therapy and its impact on rates of cytoreductive nephrectomy (CNx) and among privately insured patients with metastatic renal cell carcinoma (mRCC).
All mRCC patients aged <65 years with systemic therapy from 2004 to 2010 (n = 610) were identified from a large private insurance database. Trends in the relative utilization of immunotherapy and targeted therapy, as well as CNx treatment patterns, were compared between early (2004-2007) and late (2008-2010) periods. Multivariate logistic regression analysis identified predictors of CNx, and adjusted predicted probabilities of CNx were compared.
Among the 610 patients, 535 (87.7%) and 43 (7.1%) patients received targeted or immunotherapy alone, whereas 32 patients (5.2%) received both. A total of 145 patients (23.8%) underwent CNx. From 2004 to 2010, the annual rate of targeted therapy utilization increased markedly (from 10% to 98.2%; P <.001), whereas immunotherapy receipt declined (from 100% to 1.9%; P <.001). Annual CNx utilization peaked at 31.3% in 2005, and declined to 14.8% by 2010 (P = .045). Independent predictors receipt of CNx on multivariate analysis included age >55 years (odds ratio, 0.80; 95% confidence interval, 0.66-0.96; P = .02) and female gender (odds ratio, 0.79; 95% confidence interval, 0.63-0.99; P = .04). Notably, the predicted probability of CNx decreased between the early and late period among patients irrespective of age, gender, targeted therapy, or number of systemic therapies (P <.001 for all).
During this study period, targeted therapy has largely supplanted the use of immunotherapy among privately insured patients with mRCC treated with systemic therapy, whereas rates of CNx have declined steadily since 2005.
Copyright © 2015 Elsevier Inc. All rights reserved.
Background/Aim: In the cytokine era, cytoreductive nephrectomy (CN) improves survival for patients with metastatic renal cell carcinoma (mRCC). We analyzed the effect of CN on the survival of patients diagnosed with mRCC in the era of tyrosine kinase inhibitors (2005-present).
The Surveillance, Epidemiology, and End Results (SEER) database was used to identify adult patients diagnosed with mRCC between 2005 and 2009. The primary outcome was overall survival, analyzed with multivariable Cox models.
Out of 7,143 incident mRCC cases reported to SEER between 2005-2009, 2,629 (37%) underwent CN. Patients undergoing CN were younger, and more likely to be white, male, and married. Patients with stage T3 tumors were most likely to undergo CN (64%). Patients that underwent CN had improved one-year survival (61% vs. 22%). On multivariable analysis, CN was associated with improved overall survival(hazard ratio[HR]=0.40 95% confidence interval [CI]=0.37-0.43).
In the targeted-therapy era, patients with mRCC undergoing CN have improved survival after adjusting for tumor stage and demographic characteristics.
Objective
To evaluate the prognostic role of cytoreductive nephrectomy (CN) in patients with metastatic RCC (mRCC) and synchronous metastases, treated with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) sunitinib.
Patients and Methods
Patients with a diagnosis of metastases prior to, at the time of or within 3 months from the diagnosis of RCC and 1st-line treatment with sunitinib were included. Baseline characteristics were correlated with overall survival (OS) were through hazard ratios (HRs) estimated from univariate Cox proportional hazards models. Significant factors were then included in a multivariate Cox proportional hazards model.
Results
186 patients treated between 1/2006-3/2012 were selected. 36 (19%) had not undergone CN. CN was offered to younger patients with better prognosis. Patients who underwent CN lived significantly longer than patients without CN (median OS 23.9 [95% CI: 20.8-28.8] vs. 9 [95% CI: 4-16.4] months, p<0.001). Multivariate analysis showed that CN had an independent prognostic significance. No specific subgroup benefiting from CN was identified.
Conclusion
CN was an independent favorable prognostic factor in patients with synchronous metastases from RCC, treated with sunitinib. Information regarding the selection of mRCC patients likely to benefit from CN may be derived by ongoing phase III trials.
Objective:
Tumour characteristics, preoperative work-up and surgical treatment in patients diagnosed with renal cell carcinoma (RCC) between 2005 and 2010, and changes over time were studied in a national population-based cohort.
Material and methods:
The National Swedish Kidney Cancer Register (NSKCR) contains information on histopathology, Fuhrman grade and clinical stage at presentation, and on the preoperative work-up and surgical treatment of patients with RCC. Between 2005 and 2010, 5553 RCC patients were registered in the NSKCR, 99% of those registered in the National Cancer Registry.
Results:
During the study period the mean tumour size decreased from 70 to 64 mm (p = 0.024) and the frequency of metastatic RCC decreased from 22% to 15% (p < 0.001). The use of preoperative chest computed tomography increased from 59% to 84%. In total, 4229 (76%) patients were treated with curative intent, 3453 (82%) underwent radical nephrectomy, 606 (14%) partial nephrectomy (PN) and 170 (4%) cryotherapy or radiofrequency ablation. In tumours up to 4 cm, PN was performed in 33% of the surgically treated patients. PN irrespective of size increased from 8% to 20% and laparoscopic nephrectomy increased from 6% to 17% during the period. In patients with metastatic RCC, 55% underwent cytoreductive nephrectomy.
Conclusions:
The NSKCR explores population-based data on the clinical handling of patients with RCC. This study, between 2005 and 2010, shows significant decrease in tumour size and metastatic RCC at presentation, a more complete preoperative work-up, and significantly increased use of PN and laparoscopic nephrectomy in Sweden.
We sought to analyze utilization and survival outcomes of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) before and after introduction of targeted therapy. We identified patients with metastatic RCC between 1993 and 2010 in the SEER registry and examined temporal trends in utilization. We performed a joinpoint regression to determine when changes in utilization of cytoreductive nephrectomy occurred. We fitted multivariable proportional hazard models in full and propensity score-matched cohorts. We performed a difference-in-difference analysis to compare survival outcomes before and after introduction of targeted therapy. The proportion of patients undergoing cytoreductive nephrectomy increased from 1993 to 2004, from 29% to 39%. We identified a primary joinpoint of 2004, just prior to the introduction of targeted therapy. Beginning in 2005, there was a modest decrease in utilization of cytoreductive nephrectomy. Cytoreductive nephrectomy was associated with a lower adjusted relative hazard (0.41, 95% confidence interval 0.34 to 0.43). Median survival among patients receiving cytoreductive nephrectomy increased in the targeted therapy era (19 versus 13 months), while median survival among patients not receiving cytoreductive nephrectomy increased only slightly (4 versus 3 months). Difference-in-difference analysis showed a significant decrease in hazard of death among patients who received cytoreductive nephrectomy in the targeted therapy era. Despite decreased utilization in the targeted therapy era, cytoreductive nephrectomy remains associated with improved survival. Prospective randomized trials are needed to confirm the benefit of cytoreductive nephrectomy among patients with metastatic RCC treated with novel targeted therapies. © 2013 Wiley Periodicals, Inc.
● To determine whether patients with metastatic non-clear cell renal cell carcinoma (RCC) benefit from cytoreductive nephrectomy (CN).
● We used the Surveillance, Epidemiology, and End Results Program to identify a population-based sample of 4914 patients diagnosed with metastatic RCC between 2000-2009. ● Of these, 591 patients had non-clear cell histology. ● The median follow up was 20 months. ● The primary outcome measure was RCC-specific mortality.
● Approximately 64% of patients underwent CN. ● Patients with non-clear cell histology who underwent CN displayed lower RCC-specific and all-cause mortality than those who did not (p<.001 in both cases). ● After adjustment for age, gender, race, marital status, year of diagnosis, geographic location, and histology the associations between CN and decreased RCC-specific mortality (HR 0.62, 95% CI 0.48-0.80, p<.001) and CN and all-cause mortality (HR 0.45, 95% CI 0.37-0.55, p<.001) remained highly significant. ● Among patients diagnosed in 2006-2009 (targeted therapy era), the results remained unchanged (HR 0.50, 95% CI 0.34-0.72, p<.001 and HR 0.43, 95% CI 0.31-0.59, p<.001, respectively). ● An interaction model revealed that all histologies displayed decreased all-cause mortality with CN.
● Patients with metastatic non-clear cell RCC from the SEER program, including those treated in the targeted therapy era, appear to derive a survival benefit from CN, an association which remained significant regardless of histologic subtype. ● This observation suggests that CN remains standard in advanced RCC patients deemed to be surgical candidates.
Background:
The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models.
Methods:
We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit.
Findings:
Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6-21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68-0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4-50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7-25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5-9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639-0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636-0·687), of the French model 0·640 (0·614-0·665), of the IKCWG model 0·668 (0·645-0·692), and of the MSKCC model 0·657 (0·632-0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models.
Interpretation:
The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis.
Funding:
None.
Background:
Cytoreductive nephrectomy (CN) plays an important role in the multimodal treatment of metastatic renal cell carcinoma (RCC). However, certain patients experience rapid progression of the carcinoma following CN. This study aimed to investigate the value of neutrophil-to-lymphocyte ratio (NLR) in the selection of patients for CN.
Methods:
Records corresponding to 73 patients with metastatic RCC were retrospectively reviewed. Forty-eight patients underwent CN, and their overall survival (OS) and preoperative variables were analyzed. The OS of patients who did not undergo CN was used as a reference.
Results:
Univariate analysis showed that symptomatic tumors, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≥ 1, hemoglobin level <12 g/dl, neutrophil count ≥ 5500/μL, C-reactive protein level ≥ 2.0 mg/dl, and NLR ≥ 4.0 were significantly associated with poor outcomes in patients who underwent cytoreductive nephrectomy. The median OS of patients with NLR ≥ 4.0 was 10.2 months, which was significantly shorter than that of patients with NLR <4.0 (36.5 months) (P = 0.0020). Multivariate analysis showed that NLR and ECOG-PS were independent predictors of OS in patients treated with CN. The OS of CN patients with NLR ≥ 4.0 and ECOG-PS ≥1 was similar to that of patients who did not undergo CN (8.4 vs. 6.1 months, P = 0.939).
Conclusions:
Preoperative NLR elevation is significantly associated with poor outcomes in patients with metastatic RCC who underwent CN. Patients with NLR ≥4.0 and ECOG-PS ≥ 1 might not benefit from immediate CN after initial diagnosis.
Systemic therapy of metastatic renal cell carcinoma has completely changed in the last 5 years. Although a cure for the disease is still not achieved with systemic treatment in the majority of cases immunotherapy is no longer used. The therapeutic regiments are mainly based on angiogenic inhibitors such as sunitinib, sorafenib, pazopanib, everolimus and temsirolimus as well as the combination of bevacizumab with interferon. This article gives an overview of these treatment options and the clinical setting for their usage. To achieve a prolonged progression-free survival, a continuous therapy based on the new drugs is necessary. The major goal of the treatment remains to keep the disease stable as complete remission is only seen in 2-4% of cases. With these lengthy treatment regimes a schedule for sequenced administration of drugs is necessary for most of the patients. The optimal treatment sequence is unknown and should be chosen based on the individual course of the disease and the side effects as well as comorbidities. The role of neoadjuvant and adjuvant therapies remains unclear.
Vascular endothelial growth factor targeted therapy is a standard of care in patients with metastatic renal cell carcinoma. The role of cytoreductive nephrectomy in the era of novel agents remains poorly defined.
We retrospectively reviewed baseline characteristics and outcomes of 314 patients with anti-vascular endothelial growth factor therapy naïve, metastatic renal cell carcinoma from United States and Canadian cancer centers to study the impact of cytoreductive nephrectomy on overall survival.
Patients who underwent cytoreductive nephrectomy (201) were younger (p < 0.01), and more likely to have a better Karnofsky performance status (p < 0.01), more than 1 site of metastasis (p = 0.04) and lower corrected calcium levels (p < 0.01) compared to those who did not undergo cytoreductive nephrectomy (113). On univariable analysis cytoreductive nephrectomy was associated with a median overall survival of 19.8 months compared to 9.4 months for patients who did not undergo cytoreductive nephrectomy (HR 0.44; 95% CI 0.32, 0.59; p < 0.01). On multivariable analysis and adjusting for established prognostic risk factors the overall survival difference persisted (adjusted HR 0.68; 95% CI 0.46, 0.99; p = 0.04) in favor of the cytoreductive nephrectomy group. In subgroup analyses stratified for favorable/intermediate/poor risk criteria, patients in the poor risk group had a marginal benefit (p = 0.06). Similarly patients with Karnofsky performance status less than 80% also had a marginal survival benefit (p = 0.08).
In this retrospective study cytoreductive nephrectomy was independently associated with a prolonged overall survival of patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor targeted agents, although the benefit is marginal in those patients with poor risk features.
The benefits of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) should outweigh surgical morbidity. Even when the generally agreed upon selection criteria for CN are met, some patients do poorly after surgery. The objective of this study was to identify preoperative factors that were prognostic of outcome in patients who were being considered for CN.
The authors conducted a retrospective study to investigate the overall survival (OS) of patients who underwent CN using the OS of patients with mRCC who did not undergo CN as a referent group. Patients who underwent CN were divided into 2 groups based on when their OS diverged from that of nonsurgical patients. Chi-square analysis was used to identify variables that differed between the 2 surgical groups. Multivariate Cox proportional hazards regression was used to analyze those variables for the entire CN cohort. Risk factors were defined as preoperative variables that remained significant on multivariate analysis. The median OS and the overall risk of death were calculated based on the number of risk factors.
From 1991 to 2007, 566 patients who were eligible for or received systemic therapy underwent CN, and 110 patients received medical therapy alone. On multivariate analysis, independent preoperative predictors of inferior OS in surgical patients included a lactate dehydrogenase level greater than the upper limit of normal, an albumin level less than the lower limit of normal, symptoms at presentation caused by a metastatic site, liver metastasis, retroperitoneal adenopathy, supradiaphragmatic adenopathy, and clinical tumor classification>or=T3. Inferior OS and an increased risk of death were correlated positively with the number of risk factors. Surgical patients who had >or=4 risk factors did not appear to benefit from CN.
The authors of this report identified 7 preoperative variables that permitted them to identify patients who were unlikely to benefit from CN.
There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy.
Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS.
The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73.
This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.