Articles

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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Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohortstudy

Martínez Chanzá N, Xie W, Asim Bilen M, et al.
Lancet Oncol. 2019 Feb 28
DOI: 10.1016/S1470-2045(18)30907-0

Abstract

BACKGROUND:

An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB.

METHODS:

We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinomatreated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.

FINDINGS:

Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.

INTERPRETATION:

While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.

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State of the Future: Translational Approaches in Renal Cell Carcinoma in the Immunotherapy Era

Bakouny Z, Flippot R, Braun DA, et al.
Eur Urol Focus. 2019 Feb 28.
DOI: 10.1016/j.euf.2019.02.014

Abstract

The emergence of immune checkpoint inhibitors as treatment options for metastatic renal cell carcinoma (RCC) has significantly improved outcomes for patients, but also posed new challenges for researchers. Only a subset of patients respond to these therapies, and some who initially respond ultimately develop therapeutic resistance. In this brief report, we review and discuss the importance of novel technological advances for immunotherapy translational research in RCC. In particular, we highlight the potential of single-cellsequencing methods and novel PD-L1 tracer-based imaging modalities for biomarker discovery, as well as ex vivo tumor spheroids for the creation of tumor “immunograms”.

PATIENT SUMMARY:

Immunotherapy, which leverages a patient’s immune system to target tumors, is effective for a substantial number of patients with metastatic kidney cancer. We review novel technologies that may help in understanding why some patients do not respond to these treatments, with the goals of eventually being able to identify which patients will respond to therapy and developing strategies to overcome therapeutic resistance.

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Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma

Lalani A, Xie W, Martini D, et al.
J Immunother Cancer. 2018 Jan 22;6(1):5.
DOI: 10.1186/s40425-018-0315-0

Abstract

BACKGROUND:

An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB.

METHODS:

We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR.

RESULTS:

Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes.

CONCLUSIONS:

Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

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Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Rini B, Plimack E, Stus V, et al.
N Engl J Med. 2019 Feb 16.
DOI: 10.1056/NEJMoa1816714

Abstract

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.).

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