Articles

Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma

Singla N, Elias R, Ghandour RA, et al.
Urologic Oncology, September 2019
DOI: https://doi.org/10.1016/j.urolonc.2019.08.012

Abstract

Objective

To evaluate the pathologic response, safety, and feasibility of nephrectomy following receipt of immune checkpoint inhibition (ICI) for renal cell carcinoma (RCC).

Methods

Patients who underwent nephrectomy for RCC after exposure to nivolumab monotherapy or combination ipilimumab/nivolumab were reviewed. Primary surgical outcomes included operative time (OT), estimated blood loss (EBL), length of stay (LOS), readmission rates, and complication rates. Pathologic response in the primary and metastatic sites constituted secondary outcomes.

Results

Eleven nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. Six patients received 1 to 4 cycles of ipilimumab/nivolumab, while 5 received 2 to 12 infusions of nivolumab preoperatively. Five surgeries were performed laparoscopically, and 4 patients underwent concomitant thrombectomy. One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no detectable malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 ml, and 4 days, respectively. Four patients experienced a complication, including 3 that were addressed with interventional radiology procedures. One patient died of progressive disease >3 months after surgery, and 1 patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients.

Conclusions

Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. Timing of the nephrectomy relative to checkpoint dosing did not seem to impact outcome. Biopsies of lesions responding radiographically to ICI may warrant attention prior to surgical excision.

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Predictors of Survival Outcomes in Non-Metastatic Renal Cell Carcinoma in Latin America and Spain: A Multicentric Analysis

Stênio de Cássio Zequi , Thiago Camelo Mourão, Max Moura de Oliveira, Maria Paula Curado, Guilhermo Gueglio, Walter Henriques da Costa, Alvaro Zuñiga, Ruben Bengió, Carlos Scorticati, Francisco Rodríguez, Ana Maria Autran, Pablo Martínez, Carlos Ameri, Pablo Mingote, Fernando Pablo Secin, Ricardo decía, Isabela Werneck da Cunha, Gustavo Cardoso Guimarães, Sidney Glina, Joan Palou and Diego Abreu.
Kidney Cancer xx (20xx) x–xx
DOI 10.3233/KCA-190068
IOS Press

Abstract

Background

Renal cell carcinoma (RCC) is a lethal neoplasia. Data from Latin America are scarce, and the distinct ethnic origins of this population could affect predictive or prognostic factors.

Objective

We aim to describe a large cohort of non-metastatic renal cell carcinoma, identifying the demographic, clinical, and pathological prognostic factors for survival.

Methods

We used a multi-institutional retrospective cohort involving 5,670 patients who underwent radical or partial nephrectomy across seven Latin American countries and Spain from 1980 to 2016. The variables were compared, and Kaplan–Meier curves were used to estimate the overall survival (OS) and cancer-specific survival (CSS).

Results

The clear cell subtype represented 66.7% of RCC, followed by chromophobe (13.7%), papillary (5.2%), and others (14.4%). Furthermore, 72.3% of renal masses were <7.0 cm. The 5-year OS and 10-year OS rates were 86.1% and 69.5%, respectively. The 5-year and 10-year CSS rates were 89.9% and 81.8%, respectively. The demographic and clinical predicting factors for OS in the multivariate analysis were age (HR: 2.978), anemia (HR: 1.44), presence of symptoms at presentation (HR: 1.26), Karnofsky score ≤80 (HR: 2.12), and ASA score ≥ 3 (HR: 1.49). The pathological factors were nodal metastasis (HR: 2.14), peri-renal fat invasion (HR: 2.12), inferior vena cava invasion (HR: 1.61), histologic tumoral necrosis (HR: 1.69), and tumor size >7 cm (HR: 1.64).

Conclusions

Our findings agreed with those reported for some developed countries. We emphasize that ASA and peri-renal fat invasion as prognostic factors deserve further study. Information regarding microvascular invasion should be regularly incorporated in pathological reports.

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The Evaluation of Response to Immunotherapy in Metastatic Renal Cell Carcinoma: Open Challenges in the Clinical Practice

Raimondi A, Randon G, Sepe P, et al.
Int. J. Mol. Sci, 20(17), 4263; August 2019
DOI: https://doi.org/10.3390/ijms20174263

Abstract

Immunotherapy has changed the therapeutic scenario of metastatic renal cell carcinoma (mRCC), however the evaluation of disease response to immune-checkpoint inhibitors is still an open challenge. Response evaluation criteria in solid tumors (RECIST) 1.1 criteria are the cornerstone of response assessment to anti-neoplastic treatments, but the use of anti-programmed death receptor 1 (PD1) and other immunotherapeutic agents has shown atypical patterns of response such as pseudoprogression. Therefore, immune-modified criteria have been developed in order to more accurately categorize the disease response, even though their use in the everyday clinical practice is still limited. In this review we summarize the available evidence on this topic, with particular focus on the application of immune-modified criteria in the setting of mRCC.

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Cytoreductive Nephrectomy in Metastatic Papillary Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Graham J, Wells JC, Donskov F, et al.
European Urology Oncology, Volume 0, Issue 0. Articles in Press
DOI: https://doi.org/10.1016/j.euo.2019.03.007

Abstract

Background

There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC). This has been studied predominantly in clear-cell RCC, with more limited data on the role of CN in patients with papillary histology.

Objective

To determine the benefit of CN in synchronous metastatic papillary RCC.

Design, setting, and participants

Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) database, a retrospective analysis was performed for patients with papillary mRCC treated with or without CN.

Outcome measurements and statistical analysis

Median overall survival (OS) and progression-free survival (PFS) were determined for both patient groups. Cox regression analysis was performed to control for imbalances in individual IMDC risk factors.

Results and limitations

In total, 647 patients with papillary mRCC were identified, of whom 353 had synchronous metastatic disease. Of these, 109 patients were treated with CN and 244 were not. The median follow-up was 57.1 mo (95% confidence interval [CI] 32.9–77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2 mo (95% CI 12.0–16.1). Median OS for patients with CN was 16.3 mo, compared to 8.6 mo (p < 0.0001) in the no-CN group. When adjusted for individual IMDC risk factors, the hazard ratio (HR) of death for CN was 0.62 (95% CI 0.45–0.85; p = 0.0031). Limitations include the retrospective nature of the analysis.

Conclusions

The use of CN in patients with mRCC and papillary histology appears to be associated with better survival compared to no CN after adjustment for risk criteria. Selection of appropriate candidates for CN is crucial. A clinical trial in this rare population may not be possible.

Patient summary

In a population of patients with advanced papillary kidney cancer, we found that surgical removal of the primary kidney tumor was associated with better overall survival.

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Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial

Rini B, Powles T, Atkins M, et al.
The Lancet, Vol 393, 10189, P2404-2415, June 2019
DOI: https://doi.org/10.1016/S0140-6736(19)30723-8

Summary

Background

A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.

Methods

In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.

Findings

Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57–0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76–1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3–4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.

Interpretation

Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.

Funding

F Hoffmann–La Roche Ltd and Genentech Inc.

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Masas Renales y Cáncer Renal Localizado: Guía de la AUA

Campbell S; Uzzo RG; Allaf ME, et al.
The Lancet, Vol 20, 10, P1332-1334, October 2019
DOI: https://doi.org/10.1016/S1470-2045(19)30510-8

Propósito

Esta Guía de la Asociación Urológica Americana (AUA, American Urological Association) se centra primariamente en la evaluación y el manejo de las masas renales esporádicas clínicamente localizadas sospechosas de ser un carcinoma de células renales (RCC, renal cell carcinoma) en los adultos, incluyendo a los tumores renales sólidos que se realzan (solid enhancing renal tumors) y las masas renales quísticas complejas de los tipos Bosniak 3 y 4. Algunos pacientes con masas renales clínicamente localizadas podrán presentarse con hallazgos sugerentes de una biología agresiva del tumor o podrán ser pasados a un estadio más avanzado en la exploración o en el estudio patológico final. También se enfocarán las consideraciones en el manejo pertinentes para los urólogos en estos pacientes. Los patrones para la práctica en referencia a tales tumores también varían considerablemente. La literatura referente a la evaluación y el manejo ha venido evolucionando con rapidez. Ejemplos notables de ello incluyen a las controversias acerca del papel de la biopsia de las masas renales y las preocupaciones referentes a la sobreutilización de la nefrectomía radical. Por favor, también revisar el algoritmo para el tratamiento de las Masas Renales y el Cáncer Renal Localizado (Renal Mass and Localized Renal Cancer).

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Renal cell carcinoma treatment after first-line combinations

Porta C, Schmidinger M.
The Lancet, Vol 20, 10, P1332-1334, October 2019
DOI: https://doi.org/10.1016/S1470-2045(19)30510-8

Treatment of metastatic renal cell carcinoma has dramatically changed in the past two decades, moving from cytokine-based immunotherapy, to vascular endothelial growth factor (VEGF) pathway inhibitors, and to combinations of these inhibitors with novel immune checkpoint inhibitors. What was once defined as an “embarassment of riches” has now reached new, unexpected heights.

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Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study

Ornstein M, Pal S, Wood L, et al.
The Lancet, Vol 20, 10, P1386-1394, October 2019.
DOI: https://doi.org/10.1016/S1470-2045(19)30513-3

Summary

Background

Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor.

Methods

We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3–4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811.

Findings

Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7–14·2), the median progression-free survival was 8·8 months (95% CI 5·7–16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2).

Interpretation

Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting.

Funding

Pfizer.

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Long noncoding RNA lnc-DILC stabilizes PTEN and suppresses clear cell renal cell carcinoma progression

Zhang H, Wei P, Lv W, et al.
Cell & Bioscience, Vol 9, Article number: 81. October 2019
DOI: https://doi.org/10.1186/s13578-019-0345-4

Abstract

Background

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are crucial regulators affecting the progression of human cancers. Recently, lncRNA downregulated in liver cancer stem cells (lnc-DILC) was identified to function as a tumor suppressor inhibiting the tumorigenesis and metastasis in liver cancer and colorectal cancer. However, to date, little is known about the functional roles of lnc-DILC in modulating malignant phenotypes of clear cell renal cell carcinoma (ccRCC) cells.

Methods

lnc-DILC expression in human ccRCC tissues was detected by qRT-PCR. Overexpression and knockdown experiments were carried out to determine the effects of lnc-DILC on ccRCC cell proliferation, migration and invasion. To reveal the underlying mechanisms of lnc-DILC functions in ccRCC cells. RNA immunoprecipitation, RNA pull-down, in vivo ubiquitination, co-immunoprecipitation and western blot assays were performed.

Results

Here, we identified that lnc-DILC levels were dramatically downregulated in ccRCC tissues. Loss of lnc-DILC expression was correlated with larger tumor size, advanced tumor grade and lymph node metastasis, and also predicted worse prognosis in patients with ccRCC. Functionally, knockdown and overexpression experiments demonstrated that lnc-DILC inhibited cell proliferation, migration and invasion in ccRCC cells. Mechanistic investigation revealed that lnc-DILC bound to tumor suppressor PTEN and suppressed its degradation. lnc-DILC repressed the PTEN ubiquitination through blocking the interaction between PTEN and E3 ubiquitin ligase WWP2 and recruiting the deubiquitinase USP11 to PTEN. Moreover, we demonstrated that PTEN–AKT signaling was crucial for lnc-DILC-mediated suppressive effects.

Conclusions

In summary, our research revealed a novel mechanism by which lnc-DILC regulates PTEN stability via WWP2 and USP11, and shed light on potential therapeutic strategies by the restoration of lnc-DILC expression in patients with ccRCC.

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Adjuvant therapy in renal cell carcinoma

Gul A, Rini B
Cancer;125:2935–44. September, 2019
DOI: https://doi.org/10.1002/cncr.32144

Abstract

Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed.

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