February 2019

Cytoreductive nephrectomy: questions remain after CARMENA

Sumeet Bhanvadia, Sumanta K. Pal
Nature Reviews Urology Volume 15, pages 530–532 (2018)
DOI: 10.1038/s41585-018-0064-3

Cytoreductive nephrectomy, a standard approach for de novo metastatic renal cell carcinoma in the era of cytokine therapy, has been upheld during the age of targeted therapy on the basis of retrospective data. Now, the first level I prospective data from the CARMENA and SURTIME trials challenge this standard.

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Cytoreductive Nephrectomy — Patient Selection Is Key

Motzer RJ, Russo P.
N Engl J Med 2018; 379:481-482
DOI: 10.1056/NEJMe1806331

Metastatic renal-cell carcinoma has diverse clinical presentations ranging from incidental detection to a highly symptomatic systemic illness. Patients with metastatic renal-cell carcinoma are assigned a risk category — favorable, intermediate, or poor — on the basis of two published models containing five or six pretreatment selection factors, including presence of anemia, elevated serum calcium concentration, and degree of disability from cancer-related symptoms (performance status). This stratification provides important prognostic insight about whether patients should be treated with cytoreductive radical nephrectomy, systemic therapies, or both. Nephrectomy for stage IV disease removes the primary kidney tumor and its potential for bleeding and…

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

Bex A, Mulders P, Jewett M, et al.
JAMA Oncol. 2018 Dec 13
DOI: 10.1001/jamaoncol.2018.5543.

Abstract

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.

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Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma

Méjean A, Ravaud A, Thezenas S, et al.
N Engl J Med 2018; 379:417-427
DOI: 10.1056/NEJMoa1803675

Abstract

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.)

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Role of cytoreductive nephrectomy in the targeted therapy era: A systematic review and meta-analysis

García-Perdomo HA, Zapata-Copete JA, Castillo-Cobaleda DF.
Investig Clin Urol. 2018 Jan;59(1):2-9.
DOI: 10.4111/icu.2018.59.1.2

Abstract

PURPOSE:

To determine the effectiveness and harm of cytoreductive nephrectomy versus no intervention in patients with metastatic renal carcinoma who undergo targeted therapy to improve overall survival.

MATERIALS AND METHODS:

A search strategy was conducted in the MEDLINE, CENTRAL, Embase, HTA, DARE, NHS, and LILACS databases. Searches were also conducted for unpublished literature through references from relevant articles identified through the search, conferences, thesis databases, OpenGrey, Google Scholar, and clinicaltrials.gov, among others. Studies were included without language restrictions. The risk of bias assessment was made by using a modified Cochrane Collaboration tool. A meta-analysis of fixed effects was conducted. The expected outcomes were overall survival, quality of life, adverse effects, mortality, and progression- free survival. The measure of the effect was the hazard ratio (HR) with a 95% confidence interval (CI). The planned comparison was cytoreductive nephrectomy versus no intervention.

RESULTS:

A total of 22,507 patients were found among seven studies. Seven studies were included in the qualitative analysis (eight publications) and five in the quantitative analysis for overall survival. One study reported progression-free survival and one reported targeted therapy toxicities. A low risk of bias was shown for most of the study items. The HR for overall survival was 0.58 (95% CI, 0.50 to 0.65) favoring cytoreductive nephrectomy compared with no intervention.

CONCLUSIONS:

Cytoreductive nephrectomy is effective for improving overall survival in patients with metastatic renal carcinoma who undergo targeted therapy compared with no intervention.

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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Motzer RJ, Tannir NM, McDermott DF, et al
N Engl J Med 2018; 378:1277-1290
DOI: 10.1056/NEJMoa1712126

Abstract

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.)

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Comparative Effectiveness of Initial Surgery vs Initial Systemic Therapy for Metastatic Kidney Cancer in the Targeted Therapy Era: Analysis of a Population-based Cohort

Macleod LC, Odisho AY, Tykodi SS, et al.
Urology, Volume 113, Pages 146–152. March 2018
DOI: 10.1016/j.urology.2017.11.014

Abstract

OBJECTIVE:

To use econometric methods to assess comparative overall survival of patients with metastatic renal cell carcinoma (mRCC) managed with initial cytoreductive nephrectomy (CN) vs initial systemic therapy. Randomized data demonstrate improved survival for CN preceding cytokine-based therapy in mRCC. This benefit may be attenuated in the contemporary mRCC era given more effective systemic therapies.

METHODS:

Patients over age 65 with mRCC from the Surveillance, Epidemiology, and End Results registries linked with Medicare claims from 2006 to 2011 were categorized by initial treatment. We applied sequential survival analysis methods to assess the association between initial CN and overall survival (OS) including Cox proportional hazards models, propensity scoring, and instrumental variable analysis to account for measured and unmeasured selection bias.

RESULTS:

Of 537 patients analyzed, 190 had initial CN followed by targeted therapy and 347 had initial targeted therapy. Median OS in the initial CN group was 17.4 months (interquartile range 9.8-32.0), compared with 9.2 months (interquartile range 4.3-18.0) for initial targeted therapy. Cox proportional hazards analysis revealed initial CN was associated with improved OS (hazard ratio 0.50, 95% confidence interval [CI] 0.38-0.65). Propensity matching demonstrated a survival advantage for initial CN of 5.8 months (95% CI 1.9-9.7). Accounting for unmeasured confounding with instrumental variable analysis demonstrated a trend toward improved survival with initial CN (hazard ratio 0.29 [95% CI 0.08-1.00]).

CONCLUSIONS:

Initial CN is associated with improved survival compared with initial systemic therapy in a contemporary population-based mRCC cohort.

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Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma

Pal SK, Sonpavde G, Agarwal N, et al.
Eur Urol. 2017 Oct;72(4):557-564
DOI: 10.1016/j.eururo.2017.03.046

Abstract

BACKGROUND:

Treatment of metastatic renal cell carcinoma (mRCC) typically entails mechanistically distinct agents across the first- and second-line setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile.

OBJECTIVE:

To assess the ctDNA profile in a large cohort of mRCC patients, and to assess changes across patients receiving first-line and later lines of therapy.

DESIGN, SETTING, AND PARTICIPANTS:

We obtained the ctDNA profile in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Genomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and postfirst-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab).

RESULTS AND LIMITATIONS:

ctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57-70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%).

CONCLUSIONS:

In the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in postfirst-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications.

PATIENT SUMMARY:

Collection of circulating tumor DNA is feasible in patients with metastatic renal cell carcinoma, and analysis of a large cohort demonstrates significant changes in circulating tumor DNA profile across patients’ clinical course which may have therapeutic implications.

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American Confederation of Urology (CAU) experience in minimally invasive partial nephrectomy

Secin FP, Castillo OA, Rozanec JJ, et al.
World J Urol. 2017 Jan;35(1):57-65.
DOI: 10.1007/s00345-016-1837-z

Abstract

PURPOSE:

To describe the perioperative and oncology outcomes in a series of laparoscopic or robotic partial nephrectomies (PN) for renal tumors treated in diverse institutions of Hispanic America from the beginning of their minimally invasive (MI) PN experience through December 2014.

METHODS:

Seventeen institutions participated in the CAU generated a MI PN database. We estimated proportions, medians, 95 % confidence intervals, Kaplan-Meier curves, multivariate logistic and Cox regression analyses. Clavien-Dindo classification was used.

RESULTS:

We evaluated 1501 laparoscopic (98 %) or robotic (2 %) PNs. Median age: 58 years. Median surgical time, warm ischemia and intraoperative bleeding were 150, 20 min and 200 cc. 81 % of the lesions were malignant, with clear cell histology being 65 % of the total. Median maximum tumor diameter is 2.7 cm, positive margin is 8.2 %, and median hospitalization is 3 days. One or more postoperative complication was recorded in 19.8 % of the patients: Clavien 1: 5.6 %; Clavien 2: 8.4 %; Clavien 3A: 1.5 %; Clavien 3B: 3.2 %; Clavien 4A: 1 %; Clavien 4B: 0.1 %; Clavien 5: 0 %. Bleeding was the main cause of a reoperation (5.5 %), conversion to radical nephrectomy (3 %) or open partial nephrectomy (6 %). Transfusion rate is 10 %. In multivariate analysis, RENAL nephrometry score was the only variable associated with complications (OR 1.1; 95 % CI 1.02-1.2; p = 0.02). Nineteen patients presented disease progression or died of disease in a median follow-up of 1.37 years. The 5-year progression or kidney cancer mortality-free rate was 94 % (95 % CI 90, 97). Positive margins (HR 4.98; 95 % CI 1.3-19; p = 0.02) and females (HR 5.6; 95 % CI 1.7-19; p = 0.005) were associated with disease progression or kidney cancer mortality after adjusting for maximum tumor diameter.

CONCLUSION:

Laparoscopic PN in these centers of Hispanic America seem to have acceptable perioperative complications and short-term oncologic outcomes.

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Positive surgical margins are predictors of local recurrence in conservative kidney surgery for pT1 tumors

Marchiñena PG, Tirapegui S, Gonzalez IT, et al.
Int Braz J Urol. 2018 May-Jun;44(3):475-482.
DOI: 10.1590/S1677-5538.IBJU.2017.0039.

Abstract

OBJECTIVES:

The clinical significance of positive surgical margin (PSM) after a Nephron Sparing Surgery (NSS) is controversial. The aim of this study is to evaluate the association between PSM and the risk of disease recurrence in patients with pT1 kidney tumors who underwent NSS.

MATERIALS AND METHODS:

Retrospective cohort study. A total of 314 patients submitted to a NSS due to stage pT1 renal tumor between January 2010 and June 2015 were included. Recurrence-free survival was estimated. The Cox model was used to adjust the tumor size, histological grade, pathological stage, age, surgical margins and type of approach.

RESULTS:

Overall PSM was 6.3% (n=22). Recurrence was evidenced in 9.1% (n=2) of patients with PSM and 3.5% (n=10) for the group of negative surgical margin (NSM). The estimated local recurrence-free survival rate at 3 years was 96.4% (95% CI 91.9 to 100) for the NSM group and 87.8% (95% CI 71.9 to 100) for PSM group (p=0.02) with no difference in metastasis-free survival. The PSM and pathological high grade (Fuhrman grade III or IV) were independent predictors of local recurrence in the multivariate analysis (HR 12.9, 95%CI 1.8-94, p=0.011 / HR 38.3, 95%CI 3.1-467, p=0.004 respectively). Fuhrman grade proved to be predictor of distant recurrence (HR 8.1, 95%CI 1.6-39.7, p=0.011).

CONCLUSIONS:

The PSM in pT1 renal tumors showed to have higher risk of local recurrence and thus, worse oncological prognosis.

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