Articles

“At-risk” kidney: How surgical factors influence renal functional preservation after partial nephrectomy

Dagenais J, Bertolo R, Garisto J, et al.
Urology May 2019
DOI: 10.1111/iju.13930

Abstract

OBJECTIVE:

To investigate the influence of surgical modifiable factors on chronic kidney disease upstaging in a contemporary cohort of patients with normal and “at-risk” kidneys undergoing partial nephrectomy.

METHODS:

We reviewed 778 consecutive patients with (n = 634)/without (n = 144) chronic kidney disease or risk factors for chronic kidney disease in our institutional partial nephrectomy database. Chronic kidney disease upstaging was assessed using glomerular filtration rate measurements preoperatively and at 3–12 months postoperatively. Using a multivariate logistic regression, baseline clinicodemographic factors, and the operative measurements of excisional volume loss and warm and cold ischemia time on rates of chronic kidney disease upstaging were determined. Marginal effects were used to analyze the impact of ischemia time and generate interaction curves.

RESULTS:

Chronic kidney disease/risk factors for chronic kidney disease had equivalent rates of chronic kidney disease upstaging as the healthy kidney cohort (31.5% vs 38.2%, P = 0.15). Of the entire cohort, 2.8% were upstaged to stage IV–V chronic kidney disease. Multivariate analysis found a significant association between chronic kidney disease upstaging and excisional volume loss in both cohorts (no chronic kidney disease/risk factors for chronic kidney disease: odds ratio 1.63, P = 0.04; chronic kidney disease/risk factors for chronic kidney disease: odds ratio 1.42, P = 0.001). Only in the chronic kidney disease/risk factors for chronic kidney disease cohort, there was an association between ischemia type/duration and chronic kidney disease upstaging (odds ratio 1.04, P = 0.04). Warm ischemia began to predict an increased risk of chronic kidney disease upstaging at 17.6 min, which became statistically significant at 49 min.

CONCLUSION:

Chronic kidney disease upstaging is common after partial nephrectomy. Although volume loss unequivocally affects rates of upstaging irrespective of baseline renal function, warm ischemia time disproportionately influences “at-risk” kidneys. Therefore, strong consideration should be given to minimizing volume loss and using cold ischemia when extended clamp times are anticipated in “at-risk” kidneys.

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The Current State of Adjuvant Therapy Following Surgery for High-risk Renal Cell Carcinoma

Ridyard D, Buller D, Ristau B, et al.
European Urology Focus April 2019
10.1016/j.euf.2019.03.020

Abstract

Cancer recurs in up to 40% of patients following surgery for high-risk, locoregional renal cell carcinoma (RCC). To date, little progress has been made in identifying systemic adjuvant treatment options to reduce the mortality risk after surgery for high-risk RCC. Several randomized trials exploring the efficacy of adjuvant targeted therapies in the postoperative setting have recently reported results. We examine these trials to assess the contemporary role of targeted therapy following surgery in high-risk RCC and briefly consider trials that are currently accruing with a focus on immunotherapy agents in the adjuvant setting.

Patient summary

Kidney cancer often recurs despite initial surgery in patients with high-risk tumors. So far, adding systemic treatments such as targeted therapies after surgery has not resulted in improved survival outcomes. Future studies that include immunotherapy after surgery to reduce the risk of recurrence in patients with high-risk disease are eagerly anticipated.

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Systemic therapy in the management of localized and locally advanced renal cell carcinoma: Current state and future perspectives

Berquist S, Yim K, Ryan S, et al.
IJU May 2019
DOI: 10.1111/iju.13943

Abstract

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma have continued to evolve in two directions: (i) as adjuvant therapy (to reduce the risk of recurrence or progression in high-risk localized groups); or (ii) as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of adjuvant therapy phase III randomized clinical trials have been mixed and contradictory; nevertheless, the findings of the landmark Sunitinib Treatment of Renal Adjuvant Cancer study have led to approval of sunitinib as an adjuvant agent in the USA. In the realm of neoadjuvant therapy, presurgical tumor reduction has been shown in a number of phase II studies utilizing targeted molecular agents and in a recently published small randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for adjuvant and neoadjuvant strategies. The present article reviews the current status and future prospects of adjuvant and neoadjuvant therapy in localized and locally advanced renal cell carcinoma.

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Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution

Mollica V, Di Nunno V, Gatto L, et al.
Clin Drug Investig, April 2019
DOI: 10.1007/s40261-019-00773-w

Abstract

Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.

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Predictive value of single-nucleotide polymorphism signature for recurrence in localised renal cell carcinoma: a retrospective analysis and multicentre validation study

Wei J, Feng Z, Cao Y, et al.
Lancet Oncol. April 2019
DOI: 10.1016/S1470-2045(18)30932-X

Summary

BACKGROUND:

Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier.

METHODS:

In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients’ recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival.

FINDINGS:

Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0,749 [95% CI 0,660–0,826] in region 1, 0,734 [0,651–0,814] in region 2, and 0,736 [0,649–0,824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5,32 [95% CI 2,81–10,07] in the internal testing set, 5,39 [3,38–8,59] in the independent validation set, and 4,62 [2,48–8,61] in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0,811 [95% CI 0,756–0,861]).

INTERPRETATION:

Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence.

FUNDING:

National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.

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Frequency and Predictors of Renal Transplantation Among Patients Rendered Surgically Anephric for Sporadic Renal Cancer

Boswell T, Sharma V, Westerman M, et al.
Urology. April 2019.
DOI: 10.1016/j.urology.2018.12.037

Abstract

OBJECTIVE:

To assess the frequency of renal transplantation in patients rendered surgically anephric during treatment of renal cancers as well as the clinicopathologic factors associated with receipt of transplantation.

METHODS:

A retrospective review was conducted to identify patients rendered surgically anephric between 2001 and 2016 due to cancer in both renal units or cancer in an anatomically or functionally solitary kidney. Patient demographics, comorbidities, and cancer features were compared between patients who subsequently received a renal transplantation and those who did not. Time-to-event analysis was used to compare time to transplantation across varied identified parameters.

RESULTS:

Among 27 patients rendered anephric, 4 (15%) received a renal transplantation over a median follow-up of 21.6 months (interquartile range 7.2, 53.3). All transplanted patients were less than 70 years of age and had cT1a renal parenchymal mass at the time of nephrectomy. No patient undergoing completion nephrectomy for upper tract urothelial carcinoma received transplantation. Patients who were evaluated by the transplant service prior to nephrectomy were more likely to eventually undergo transplantation (60% vs 5%; P < .01). On time-to-event analyses, a cT1a renal parenchymal mass (P < .01) and a pre-nephrectomy transplant evaluation (P < .01) were associated with receipt of a transplant.

CONCLUSION:

Patients rendered anephric via nephrectomy for cancer are more likely to receive renal transplantation if they are less than 70 years old, have a cT1a renal parenchymal mass, and receive transplant consultation before nephrectomy. These data may inform future patient counseling.

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Selecting Patients with Small Renal Masses for Active Surveillance: A Domain Based Score from a Prospective Cohort Study

Sotimehin A, Patel H, Alam R, et al.
J Urol. May 2019
DOI: 10.1097/JU.0000000000000033

Abstract

PURPOSE:

We sought to identify predictors of active surveillance in a prospective cohort study of patients with a small renal mass demonstrating favorable outcomes. We generated a summary score to discriminate patients selected for active surveillance or primary intervention.

MATERIALS AND METHODS:

We analyzed the records of 751 patients from 2009 to 2018 who were enrolled in the DISSRM (Delayed Intervention and Surveillance for Small Renal Masses) Registry to compare active surveillance and primary intervention in the domains of demographics, tumor characteristics, comorbidity and patient reported quality of life. Regression models were created to assess univariable and multivariable model discrimination by the AUC and quality by the AIC (Akaike information criterion). The DISSRM score was based on the most predictive combination of variables and validated for its association with overall survival by Kaplan-Meier survival curves and a Cox proportional hazards regression model.

DESIGN, SETTING, AND PARTICIPANTS:

Multicenter retrospective analysis of 653 patients aged >75 yr who underwent PN (REnal SURGery in Elderly [RESURGE] Group).

RESULTS:

Of the patients 410 (55%) elected active surveillance and 341 (45%) elected primary intervention. Of the domains patient age, the Charlson comorbidity index, tumor diameter and the SF-12® Physical Component Score had the greatest discrimination for clinical selection into active surveillance. These domains made up the DISSRM score (AUC 0.801). The maximum DISSRM score was 7. The average score for active surveillance was 4.19 (median 4, IQR 2–6) and 72% of scores were 4 or greater. The average score for primary intervention was 3.03 (median 3, IQR 1–5) and 63% of scores were 3 or less. A higher DISSRM score was associated with worse overall survival, for example a score of 6-7 had a HR of 10.45 (95% CI 1.25–87.49, p = 0.03).

CONCLUSIONS:

The DISSRM score represents a measure of oncologic and competing risks of death in various important domains in patients with a small renal mass. It could be used to guide the management selection. Patients with intermediate scores that express illness uncertainty may require additional workup, such as confirmatory biopsy, to reach a treatment decision.

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Trifecta Outcomes of Partial Nephrectomy in Patients Over 75 Years Old: Analysis of the REnal SURGery in Elderly (RESURGE) Group

Bindayi A, Autorino Rb, Capitanio U, et al.
Eur Urol Focus Feb 2019.
DOI: 10.1016/j.euf.2019.02.010

Abstract

BACKGROUND:

Partial nephrectomy (PN) in elderly patients is underutilized with concerns regarding risk of complications and potential for poor outcomes.

OBJECTIVES:

To evaluate quality and functional outcomes of PN in patients >75 yr using trifecta as a composite outcome of surgical quality.

DESIGN, SETTING, AND PARTICIPANTS:

Multicenter retrospective analysis of 653 patients aged >75 yr who underwent PN (REnal SURGery in Elderly [RESURGE] Group).

INTERVENTION:

PN.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Primary outcome was achievement of trifecta (negative margin, no major [Clavien ≥3] urological complications, and ≥90% estimated glomerular filtration rate [eGFR] recovery). Secondary outcomes included chronic kidney disease (CKD) stage III and CKD upstaging. Multivariable analysis (MVA) was used to assess variables for achieving trifecta and functional outcomes. Kaplan-Meier survival analysis (KMA) was used to calculate renal functional outcomes.

RESULTS AND LIMITATIONS:

We analyzed 653 patients (mean age 78.4 yr, median follow-up 33 mo; 382 open, 157 laparoscopic, and 114 robotic). Trifecta rate was 40.4% (n = 264). Trifecta patients had less transfusion (p < 0.001), lower intraoperative (5.3% vs 27%, p < 0.001) and postoperative (25.4% vs 37.8%, p = 0.001) complications, shorter hospital stay (p = 0.045), and lower ΔeGFR (p < 0.001). MVA for predictive factors for trifecta revealed decreasing RENAL nephrometry score (odds ratio [OR] 1.26, 95% confidence interval 1.07–1.51, p = 0.007) as being associated with increased likelihood to achieve trifecta. Achievement of trifecta was associated with decreased risk of CKD upstaging (OR 0.47, 95% confidence interval 0.32–0.62, p < 0.001). KMA showed that trifecta patients had improved 5-yr freedom from CKD stage 3 (93.5% vs 57.7%, p < 0.001) and CKD upstaging (84.3% vs 8.2%, p < 0.001). Limitations include retrospective design.

CONCLUSIONS:

PN in elderly patients can be performed with acceptable quality outcomes. Trifecta was associated with decreased tumor complexity and improved functional preservation.

PATIENT SUMMARY:

We looked at quality outcomes after partial nephrectomy in elderly patients. Acceptable quality outcomes were achieved, measured by a composite outcome called trifecta, whose achievement was associated with improved kidney functional preservation.

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Partial nephrectomy vs cryoablation for T1a renal cell carcinoma: A comparison of survival benefit stratified by tumour size

Liao X, Qiu S, Wang W, et al.
Cancer Epidemiology. April 2019.
DOI: 10.1016/j.canep.2019.02.016

Abstract

OBJECTIVES:

We compared the impact on survival outcomes of partial nephrectomy (PN) and cryoablation (CA) for patients diagnosed with T1a renal cell carcinoma (RCC).

PATIENTS AND METHODS:

Among patients diagnosed between 2004 and 2014 in the Surveillance, Epidemiology and End Results program, we identified histologically confirmed T1aN0M0 RCC treated with PN (n = 17644) or CA (n = 868). Propensity score matching (PSM) was performed. Kaplan-Meier method, Cox proportional hazards model were used to calculate cancer specific mortality (CSM) and overall mortality (OM) in the unmatched and matched cohort, and in subgroups based on tumour size (< 2 cm, 2-3 cm, 3-4 cm). Sensitivity analyses were performed.

RESULTS:

A total of 18512 patients were identified: PN (93.88%) and CA (6.12%). In the propensity-score matched cohort, for tumours ≤ 2 cm, the CA and PN groups had similar CSM (HR: 1.41, 95% CI: 0.32–6.31, p = 0.65) and OM (HR 0.97, 95%CI: 0.47–2.01, p = 0.93). For tumours 2-3 cm, CA was associated with similar CSM (HR 1.64, 95%CI: 0.67–4.03, p = 0.28) but higher OM (HR 2.05, 95%CI: 1.35–3.11, p < 0.001), compared with PN. For tumours 3-4 cm, CA was associated with increased CSM (HR: 3.76, 95% CI: 1.62–8.69, p = 0.002) and OM (HR 2.17, 95%CI: 1.48–3.18, p < 0.001).

CONCLUSIONS:

For RCC ≤ 2 cm, PN and CA are equal in survival outcomes. For RCC 2-4 cm, PN may have a possible advantage over CA.

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Conditional survival of patients with small renal masses undergoing active surveillance

Petros F, Venkatesan A, Kaya D, et al.
BJUI. March 2019.
DOI: 10.1111/bju.14486

Abstract

OBJECTIVES:

To determine conditional survival for patients with small renal masses (SRMs) undergoing active surveillance (AS).

MATERIALS AND METHODS:

Patients were enrolled in a prospective AS protocol at our institution between May 2005 and January 2016. Patients with SRMs ≤4 cm with serial cross-sectional imaging available in-house for review were included. Overall survival (OS) was estimated using the Kaplan–Meier method and modelled via Cox proportional hazards models. The primary endpoints analysed were the conditional probability of survival and tumour growth over time. Landmark analysis was used to evaluate survival outcomes beyond the 2-year mark after the initial scan. The relative conditional survival of patients on AS was compared to those undergoing partial nephrectomy (PN) using inverse probability of treatment weighting.

RESULTS:

A total of 272 patients were included in this analysis. The mean initial SRM size was 1.74 ± 0.77 cm, and the mean mass size closest to the 2-year mark was 1.97 ± 0.83 cm. The likelihood of continued survival to 5 years improved after the 2-year landmark. Patients with masses <3 cm who survived the first 2 years on AS had a 0.84–0.85 chance of surviving to 5 years, and if they survived 3 years, the probability of surviving to 5 years improved to 0.91. A slow tumour growth (β: 0.12; P < 0.001) with parallel growth rates was found for tumours <3 cm. Patients on AS and those who underwent PN had similar OS for ~7 years, beyond which PN demonstrated a trend of lower risk of death compared with AS (hazard ratio 0.57; P = 0.07).

CONCLUSIONS:

The conditional survival probability of patients with SRMs <3 cm on AS increased after 2 years. This information may prove useful to urologists and patients who are considering continuing AS vs intervention after the first 2 years on AS.

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