Articles

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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Renal transplantation: management of renal tumor in the graft and in the native kidney

García Marchiñena P, Romeo A, Martínez P, et al.
Rev.Arg.de Urol.·Vol.79(4)2014

Abstract

OBJECTIVES:

To describe the characteristics, forms of presentation and therapeutic management in transplanted patients treated for renal tumor in our hospital.

MATERIALS AND METHODS:

We conducted a retrospective analysis of 10 patients who underwent renal transplantation and developed a renal tumor between January 2010 and June 2014. The collection of data was carried through history electronic medical records of our hospital (Intranet).

RESULTS:

During the study period, 796 patients were treated for a kidney tumor in our hospital; 10 of these cases occurred in renal transplant patients. 90% were men. Average age was 40 years. Average time kidney transplantation/tumor was 14 years. 80% of the tumors were incidental. 90% had localized disease. Half of the patients (n=5) included in this series had one or more tumors in the native kidneys, while the other 50% had a tumor in the graft. All patients (n=5) with native kidney tumor underwent laparoscopic radical nephrectomy. Graft tumor: renal explant (n=1), partial nephrectomy conventional route (n=3) and active surveillance (n=1). 46% (n=6) of the tumors corresponded to clear cell renal carcinoma variety. The other 7 (54%) tumors corresponded to papillary variety. The average follow-up of patients was 14.7 months. Surgical patients (n=9) underwent 88.8% (n=8) developed favorably.

CONCLUSIONS:

Renal tumors in transplant patients are characterized by incidental diagnosis and a higher proportion of papillary types. The treatments for these patients are similar to the general population.

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Interdisciplinary Management of Renal Cell Carcinoma Associated to Von Hippel-Lindau Disease

Daruich M, García Marchiñena P, Jurado A, Gueglio G
Rev. Arg. de Urol. · Vol. 81 (3) 2016

Abstract

OBJECTIVES:

We aimed to describe the clinical characteristics of patients with Von Hippel-Lindau disease, evaluated by the “Von Hippel-Lindau disease interdisciplinary management group” of a Latin American hospital, noting the management and behavior of renal cell carcinoma associated with this syndrome.

MATERIALS AND METHODS:

A retrospective observational descriptive study was conducted. We included all patients with clinical diagnosis of this disease evaluated during the period from August 2014 to August 2015.

RESULTS:

Eleven patients were included. Mean age of first manifestation was 30 (17-56) years. The initial clinical manifestations were hypertension (54.5% [n=4]), neurological symptoms (18.1% [n=2]), eye symptoms (18.1% [n=2]) and others (27.2% [n=3]). A family history was detected in 81.8% (n=9) of cases. The 54.5% (n=6) of the patients developed renal cell carcinoma with an average of 2.5 (1-5) surgeries per patient. The 81.8% (n=9) of these procedures were open procedures. The mean resected tumors per procedure was 3 (1-8). One patient began hemodialysis and another patient developed metastasis. Mean follow- up was 7.5 (1-26) years.

CONCLUSIONS:

The interdisciplinary management of renal cell carcinoma associated with Von Hippel-Lindau disease could prevent and differ the sequelae associated, not only to the loss of kidney function, but also in other organs involved in the disease, improving the quality of life of these patients.

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Current patterns of presentation and treatment of renal masses: a clinical research office of the endourological society prospective study

Laguna MP, Algaba F, Cadeddu J, et al.
J Endourol. 2014 Jul;28(7):861-70.
DOI: 10.1089/end.2013.0724

Abstract

PURPOSE:

To assess epidemiologic characteristics, clinical and pathologic patterns of presentation, and treatment strategies in a contemporary population with renal masses (RMs).

METHODS:

The Clinical Research Office of the Endourological Society collected prospective epidemiologic, clinical, and pathologic data on consecutive patients with RMs who were treated during a 1-year period in 98 centers worldwide. Preoperative assessment and treatment were performed according to local clinical practice guidelines.

RESULTS:

From January 2010 to February 2012, 4288 patients (4355 cases, 4815 tumors) were treated for a RM. The mean age of the cohort was 61.5 years, and the ratio male:female 1.8:1. Caucasians represented 75% of the population, and the median body mass index was 27. The cohort exhibited a high rate of comorbidity (65.6%), including a 48.5% rate of hypertension; one-third of patients had a combination of two or more comorbidities. One-third of patients (36%) had risk factors for renal-cell carcinoma (RCC), of which smoking and obesity were the most common. Diagnosis was incidental in 67% of cases, and 22.2% of cases had chronic kidney disease stage ≥III at presentation. Median radiologic size was 44 mm (range 2-300 mm) and 68% were cT1. Radical nephrectomy and nephron-sparing surgery (NSS) including ablation were performed in 52% and 46% of cases, respectively, while 3.6% of cases were actively surveyed. Median pathologic size was 43 mm (range 2-300 mm) and 63% of the RCCs were pT1.

CONCLUSIONS:

Current patterns of presentation of RMs are consistent with the decreasing trends in age and clinical or pathologic size and increasing incidental diagnosis. Patients exhibit a considerable basal comorbidity and presence of risk factors for RCC. Half of the cases are treated by a nephron-sparing modality with an increase in the penetration of NSS techniques in the contemporary urologic practice.

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Circulating Fibroblast Growth Factor 21 (Fgf21) as Diagnostic and Prognostic Biomarker in Renal Cancer

Knott ME, Minatta JN, Roulet L, et al.
J Mol Biomark Diagn. 2016 Jun;1(Suppl 2).
DOI: 10.4172/2155-9929.S2-015

Abstract

BACKGROUND:

The finding of new biomarkers is needed to have a better sub-classification of primary renal tumors (RCC) as well as more reliable predictors of outcome and therapy response. In this study, we evaluated the role of circulating FGF21, an endocrine factor, as a diagnostic and prognostic biomarker for ccRCC.

MATERIALS AND METHODS:

Serum samples from healthy controls (HC), clear cell and chromophobe RCC cancer patients were obtained from the serum biobank “Biobanco Público de Muestras Séricas Oncológicas” (BPMSO) of the “Instituto de Oncología “Ángel H. Roffo”. Serum FGF21 and leptin were measured by ELISA while other metabolic markers were measured following routinely clinical procedures.

RESULTS:

One of our major findings was that FGF21 levels were significantly increased in ccRCC patients compared with HC. Moreover, we showed an association between the increased serum FGF21 levels and the shorter disease free survival in a cohort of 98 ccRCC patients, after adjustment for other predictors of outcome.

CONCLUSIONS:

Our results suggest that higher FGF21 serum level is an independent prognostic biomarker, associated with worse free-disease survival.

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