Artículos

Roderick Emile De Bruijna, Peter Muldersb, Michael A. Jewett, et al

European Urology, 2019
DOI: 10.1016/j.eururo.2019.06.006

Abstract

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.

Stênio de Cássio Zequi, Walter Henriques da Costa , Fernando Korkes, Rodolfo Borges dos Reis, Wilson Francisco Schreiner Busato, Wagner Eduardo Matheus, Deusdedit Cortez Vieira da Silva Neto, Felipe de Almeida e Paula, Gustavo Franco Carvalhal, Lucas Nogueira, Roni de Carvalho Fernandes, Adriano Gonçalves e Silva, André Deeke Sasse, André P. Fay, Denis Leonardo Jardim, Diogo Assed Bastos, Diogo Augusto Rodrigues da Rosa, Evanius Wierman, Fabio Kater, Fabio A. Schutz, Fernando Cotait Maluf, Fernando Nunes Galvão de Oliveira, Igor Alexandre Protzner Morbeck, José Augusto Rinck, Karine Martins da Trindade, Manuel Caitano Maia, Vinicius Carrera Souza, Fernando Sabino Marques Monteiro and Andrey Soares.

Abstract

Background:

Renal cell cancer (RCC) is one of the 10 most common cancers in the world, and its incidence is increasing, whereas mortality is declining only in developed countries. Therefore, two collaborative groups, The Latin American Oncology Cooperative GroupGenitourinary Section (LACOG-GU) and the Latin American Renal Cancer Group (LARCG), held a consensus meeting to develop this guideline.

Methods:

Issues (134) related to the treatment of RCC were previously formulated by a panel of experts. The voting panel comprised 26 specialists (urologists and medical oncologists) from the LACOG-GU/LARCG. A consensus was reached if 75% agreement was achieved. If there was less concordance, a new discussion was undertaken, and a consensus was determined by the most votes after a second voting session.

Results:

The expert meeting provided recommendations that were in line with the global literature; 75.0% of the recommendations made by the panel of experts were evidence-based level A, 22.5% of the recommendations were level B, and 2.5% of the recommendations were level D.

Conclusions:

This review suggests recommendations for the surgical treatment of RCC according to the LACOG-GU/LARCG experts.

Verbiest A, Renders I1, Caruso S, et al.

Clinical Genitourinary Cancer, 2019
DOI: 10.1016/j.clgc.2019.05.009

Abstract

Introduction:

Recent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.

Patients and Methods:

Patients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.

Results:

In total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.

Conclusion:

In accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.

Correa A, Jegede O, Haas N, et al.

Journal of Clinical Oncology, June 2019.
DOI: 10.1200/JCO.19.00107

Abstract

PURPOSE:

To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) adjuvant trial.

PATIENTS AND METHODS:

Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System [UISS]; Stage, Size, Grade, and Necrosis [SSIGN]; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center [MSKCC]; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities.

RESULTS:

Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis.

CONCLUSION:

In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.

Hidekazu Tachibana, Tsunenori Kondo, Hiroki Ishihara, et al.

Clinical Genitourinary Cancer, August 2019
DOI: 10.1016/j.clgc.2019.04.004

Abstract

Introduction:

There is scarce information regarding nivolumab treatment for metastatic renal cell carcinoma (mRCC) in patients with end-stage renal disease (ESRD). This study investigated the safety and efficacy of nivolumab in patients with mRCC and ESRD.

Materials and Methods:

This 2-center retrospective study evaluated 62 patients who were administered nivolumab for mRCC between June 2013 and August 2018. The ESRD group (n = 7) and non-ESRD group (n = 55) were compared in terms of their immune-related adverse events (irAEs), objective response rate, progression-free survival, and overall survival.

Results:

All 7 patients with ESRD were male (median age, 67 years; range, 52-73 years), and their median duration of nivolumab use was 6.0 months (range, 1.8-8.2 months). One patient experienced a partial response, and 4 patients had stable disease. The objective response rate was lower in the ESRD group than in the non-ESRD group (16.7% vs. 37.5%; P = .25). Relative to the non-ESRD group, the ESRD group had slightly lower rates of all irAEs (42.9% vs. 58.7%) and grade 3 or higher irAEs (14.3% vs. 21.7%). The irAEs in the ESRD group were skin rash (grade 1), diarrhea (grade 1), and severe fatigue (grade 3) after the first nivolumab infusion, which required treatment discontinuation. The Kapan-Meier curves revealed no significant differences between the ESRD and non-ESRD groups in terms of progression-free (P = .63) and overall survival (P = .62).

Conclusion:

It may be possible to safely and effectively use nivolumab for select patients with mRCC and ESRD.

García Marchiñena P, Tobia I, Abreu D, et al.

Actas Urológicas Españolas 2019
DOI: 10.1016/j.acuro.2019.01.005

Introducción y objetivos:

El objetivo de este estudio es evaluar las tasas de sobrevida global (OS), la sobrevida específica del cáncer (CSS), la sobrevida libre de recaída global (RFS), la sobrevida tiempo libre hasta la recaída local (LRFS) y la sobrevida tiempo libre hasta la recaída a distancia (DRFS), en los pacientes con carcinoma de células renales (CCR) pT3a considerando a la infiltración de grasa (FI) perirrenal y/o sinusal como factores pronósticos.

Materiales y métodos:

Cohorte retrospectiva de pacientes con CCR pT3a sometidos a cirugía. Los datos se extrajeron de la base de datos LARCG. Se evaluaron variables demográficas, clínicas, patológicas y quirúrgicas. La FI se dividió en 4 grupos (vena, perirrenal, sinusal y ambas grasas). Se realizaron curvas de Kaplan-Meier y regresión de Cox.

Resultados:

Se incluyeron 293 pacientes. La edad media fue de 61,4 años. La mediana de seguimiento fue de 21 meses (r: 1-194). La CSS, la RFS, el LRFS y el DRFS estimadas a 3 años en el grupo de ambas grasas infiltradas fueron 53,1, 45,1, 58,7 y 51,6 meses, respectivamente, en todos los casos estadísticamente inferiores al resto (p˂0,005). En el análisis multivariable, la infiltración de ambas grasas tuvo un aumento significativo de mortalidad específica, recaída global y local con respecto a infiltración de venas (HR: 4,5, 2,42 y 8,08, respectivamente). El grado de Fuhrman y la infiltración de la pelvis renal fueron predictores independientes de la CSS y la RFS.

Conclusiones:

La infiltración de ambas grasas renales aumenta el riesgo de recaída global y local en pT3a RCC. Del mismo modo, se asocia con una menor sobrevida específica del cáncer, debiendo considerarse como un factor de mal pronóstico.

A Systematic Review and Meta-analysis

Wang Y, Zhou S, Yang F, et al

JAMA Oncol. 2019.
DOI:10.1001/jamaoncol.2019.0393

Abstract

IMPORTANCE:

Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice.

OBJECTIVE:

To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.

Data Sources  PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.

STUDY SELECTION:

Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.

DATA EXTRACTION AND SYNTHESIS:

Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.

MAIN OUTCOMES AND MEASURES:

Incidences of treatment-related adverse events and differences between different drugs and cancer types.

RESULTS:

This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).

CONCLUSIONS AND RELEVANCE:

Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

Zhang X, Yin X, Zhang H, et al.

BMC Cancer April 2019
DOI: 10.1186/s12885-019-5578-4

Abstract

BACKGROUND:

In clinical practice, the detection of biomarkers is mostly based on primary tumors for its convenience in acquisition. However, immune checkpoints may express differently between primary and metastatic tumor. Therefore, we aimed to compare the differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastatic sites of renal cell carcinoma (RCC).

METHODS:

Patients diagnosed with RCC by resection or fine needle aspiration of metastasis were included. Immunohistochemistry (IHC) was applied to detect PD-1, PD-L1 and PD-L2 expressions. SPSS 22.0 was applied to conduct Chi-square, consistency tests and Cox’s proportional hazards regression models. GraphPad Prism 6 was used to plot survival curves and R software was used to calculate Predictive accuracy (PA).

RESULTS:

In the whole cohort (N = 163), IHC results suggested a higher detection rate of PD-L1 in the metastasis than that of the primary site (χ2 = 4.66, p = 0.03), with a low consistent rate of 32.5%. Among different metastatic tumors, PD-1 was highly expressed in the lung/lymph node (65.3%) and poorly expressed in the brain (10.5%) and visceral metastases (12.5%). PD-L1 was highly expressed in lung/lymph node (37.5%) and the bone metastases (12.2%) on the contrary. In terms of survival analysis, patients with PD-1 expression either in the primary or metastasis had a shorter overall survival (OS) (HR: 1.59, 95% CI 1.08–2.36, p = 0.02). Also, PD-L1 expression in the primary was associated with a shorter OS (HR 2.55, 95% CI 1.06–6.15, p = 0.04). In the multivariate analysis, the predictive accuracy of the whole model for PFS was increased from 0.683 to 0.699 after adding PD-1.

CONCLUSION:

PD-1, PD-L1 and PD-L2 were differentially expressed between primary and metastatic tumors. Histopathological examination of these immune check points in metastatic lesions of mRCC should be noticed, and its accurate diagnosis may be one of the effective ways to realize the individualized treatment.

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.

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.