Articles

Predicting Renal Cancer Recurrence: Defining Limitations of Existing Prognostic Models With Prospective Trial-Based Validation

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.

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Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma and End-stage Renal Disease at 2 Centers

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.

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Valor pronóstico de la invasión de grasa perirrenal y/o del seno en pacientes con carcinoma de células renales pT3a: estudio de cohorte multicéntrico. Grupo LARCG

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.

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Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials

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.

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Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition Is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma

Albiges L, Powles T, Staehler M.
European Urology August 2019
DOI: 10.1016/j.eururo.2019.05.022

Abstract

Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies.

Patient summary

Pembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naïve). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

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Differential expressions of PD-1, PD-L1 and PD-L2 between primary and metastatic sites in renal cell carcinoma

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.

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“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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