Articles

Non-contrast imaging characteristics of papillary renal cell carcinoma: implications for diagnosisand subtyping

Badri AV, Waingankar N, Edwards K, et al.
Can J Urol. 2019 Oct;26(5):9916-9921.

Abstract

Introduction

Current radiographic guidelines suggest unenhanced renal lesions < 20 Hounsfield Units (HU) are overwhelmingly benign, requiring no further evaluation. We evaluate our experience with papillary renal cell carcinoma (pRCC) presenting with low pre-contrast attenuation and the relationship of attenuation with histologic pRCC subtype.

Materials and Methods

We reviewed our institutional kidney cancer database for patients with pT1 or pT2 pRCC between 2003-2017. Tumors were categorized by papillary subtype by expert uropathologists. Preoperative CT images were analyzed at six regional tumor locations. Low, presumably benign, unenhanced median attenuation was defined as ≤ 20 HU. We calculated the frequency of pRCC with low attenuation and assessed the relationship between attenuation and pRCC subtype using logistic regression.

Results

Sixty-one patients with evaluable imaging were included. Median tumor size was 6 cm (1.7 cm-15.3 cm) with 39% (n = 24) type-1 and 61% (n = 37) type-2. Half of all pRCC tumors (n = 30) exhibited very low pre-contrast attenuation (< 20 HU), risking misdiagnosis as benign using current guidelines. Of these, 80% (n = 24) were type-2 with significant biological potential. Overall, type-2 tumors demonstrated a lower pre-contrast attenuation than type-1 (median HU: 19.8 (1.5-42.3) versus 29.6 HU (10-45.8), p < 0.01; max HU: 25.3 versus 36.5 HU, p < 0.01). After adjustment, lower pre-contrast HU was an independent predictor of pRCC subtype associated with a 5.5-fold increase of being type-2 (OR = 5.47, p < 0.01).

Conclusion

pRCCs may exhibit very low attenuation on pre-contrast CT. This appears more common among the more aggressive type-2 subtype. These data suggest that low attenuation (< 20 HU) alone on non-contrast CT imaging is insufficient as a single parameter to rule out malignancy.

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First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Resultsfrom the International Metastatic Renal-cell Carcinoma Database Consortium

Dudani S, Graham J, Wells JC, et al.
Eur Urol. 2019 Dec;76(6):861-867.
DOI: 10.1016/j.eururo.2019.07.048. Epub 2019 Aug 22.

Abstract

Background

In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited.

Objective

To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies.

Design, setting, and participants

Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo.

Intervention

All patients received first-line IO combination therapies.

Outcome measurements and statistical analysis

First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors.

Results and limitations

In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] -8% to 22%, p =  0.4), TTF was 14.3 versus 10.2 mo (p =  0.2), TNT was 19.7 versus 17.9 mo (p =  0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46-1.12, p =  0.14), 0.65 (95% CI 0.38-1.11, p =  0.11), and 1.74 (95% CI 0.82-3.68, p =  0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3-57%, p =  0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p =  0.4; n = 55). Limitations include the study’s retrospective design and sample size.

Conclusions

There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially.

Patient summar

There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinomareceiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

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

Correa AF, Jegede O, Haas NB, et al.
J Clin Oncol. 2019 Aug 10;37(23):2062-2071.
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.

Conclusions

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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Management of Renal Masses and Localized Renal Cancer: Systematic Review and Meta-Analysis

Pierorazio PM, Johnson MH, Patel HD, et al.
J Urol. 2016 Oct;196(4):989-99.
DOI: 10.1016/j.juro.2016.04.081.

Abstract

Purpose

Several options exist for management of clinically localized renal masses suspicious for cancer, including active surveillance, thermal ablation and radical or partial nephrectomy. We summarize evidence on effectiveness and comparative effectiveness of these treatment approaches for patients with a renal mass suspicious for localized renal cell carcinoma.

Materials and methods

We searched MEDLINE®, Embase® and the Cochrane Central Register of Controlled Trials from January 1, 1997 through May 1, 2015. Paired investigators independently screened articles to identify controlled studies of management options or cohort studies of active surveillance, abstracted data sequentially and assessed risk of bias independently. Strength of evidence was graded by comparisons.

Results

The search identified 107 studies (majority T1, no active surveillance or thermal ablation stratified outcomes of T2 tumors). Cancer specific survival was excellent among all management strategies (median 5-year survival 95%). Local recurrence-free survival was inferior for thermal ablation with 1 treatment but reached equivalence to other modalities after multiple treatments. Overall survival rates were similar among management strategies and varied with age and comorbidity. End-stage renal disease rates were low for all strategies (0.4% to 2.8%). Radical nephrectomy was associated with the largest decrease in estimated glomerular filtration rate and highest incidence of chronic kidney disease. Thermal ablation offered the most favorable perioperative outcomes. Partial nephrectomy showed the highest rates of urological complications but overall rates of minor/major complications were similar among interventions. Strength of evidence was moderate, low and insufficient for 11, 22 and 30 domains, respectively.

Conclusions

Comparative studies demonstrated similar cancer specific survival across management strategies, with some differences in renal functional outcomes, perioperative outcomes and postoperative harms that should be considered when choosing a management strategy.

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A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer

Lin J, Song AJ, Hoffman-Censits J, et al.
Am J Clin Oncol. 2020 Feb;43(2):82-86.
DOI: 10.1097/COC.0000000000000636.

Abstract

Objectives

There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors.

Materials and methods

mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry.

Results

Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92).

Conclusion

Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.

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Impact of Patients’ Gender on Efficacy of Immunotherapy in Patients With Metastatic Kidney Cancer: A Systematic Review and Meta-analysis.

Hassler MR1, Abufaraj M2, Kimura S, et al.
Clin Genitourin Cancer. 2019 Sep 27.
DOI: 10.1016/j.clgc.2019.09.004.

Abstract

Recent meta-analyses on checkpoint inhibitors in cancer report conflicting data regarding the association of patient gender with inhibitor efficacy. In advanced kidney cancer, checkpoint inhibitors have shown improved outcomes in first- and second-line settings compared with standard of care, but the role of patient gender on treatment outcome is unclear. We aimed to assess the efficacy of immunotherapyaccording to patient gender in advanced kidney cancer. We performed a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed using PubMed, Scopus, Web of Science, and The Cochrane Library to identify eligible studies published through February 16, 2019. Studies were included if they reported on the differential outcomes of male and female patients with metastatic kidney cancer receiving immunotherapy. Our outcomes of interest were overall survival (OS) or progression-free survival (PFS). Four randomized controlled trials comprising a total of 3664 patients (2715 males and 949 females) met our inclusion criteria. Both men and women with metastatickidney cancer had an OS and PFS advantage with immunotherapy compared with standard-of-care, but no statistically significant difference between the genders was observed (OS hazard ratio [HR] for men, 0.69; 95% confidence interval [CI], 0.59-0.8; P = .40; HR for women, 0.62; 95% CI, 0.48-0.81; P = .13; PFS HR for men, 0.7; 95% CI, 0.59-0.82; P = .24; HR for women, 0.68; 95% CI, 0.52-0.90; P = .105). In patients with advanced kidney cancer receiving checkpoint inhibitors, there seems to be no association of patient genderwith treatment outcome.

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Prognostic and predictive molecular biomarkers in metastatic renal cell carcinoma patients treatedwith immune checkpoint inhibitors: a systematic review

Rebuzzi SE, Perrone F, Bersanelli M, et al.
Expert Rev Mol Diagn. 2019 Oct 24:1-17.
DOI: 10.1080/14737159.2019.1680286.

Abstract

Introduction

In recent years, the treatment landscape of metastatic renal cell carcinoma (mRCC) has been improved using immune-checkpoint inhibitors (ICI). Nevertheless, the number of patients experiencing clinical benefit from immunotherapy is still limited, while others obtain more benefit from tyrosine kinase inhibitors (TKI). The identification of prognostic and predictive factors would be crucial to better select patients most likely to benefit from immunotherapy among the other potentially available therapeutic options.

Areas covered

This systematic review summarizes the current knowledge (2010–2019) on molecular prognostic and predictive biomarkers, assessed in peripheral blood and/or from tumor tissue, in mRCC patients treated with ICI.

Expert opinion

Among all the biomarkers analyzed, PD-L1 expression on tumor tissue is the most studied. It has an unfavorable prognostic role for patients treated with TKI, which seems to be overcome by ICI-based combinations. Nevertheless, no clear predictive role of immunotherapy efficacy has been observed for PD-L1 in mRCC. Emerging evidence regarding pro-angiogenic or pro-immunogenic genomic and transcriptomic signatures suggests a potential predictive role in patients treated with ICI-based combinations. The rationale for TKI-ICI combinations is based on tumor microenvironment and genomic background, which represent the target of these two main therapeutic options for mRCC.

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First-Line Systemic Therapy for Metastatic Clear-Cell Renal Cell Carcinoma: Critical Appraisal of Emerging Options

Loo V, Salgia M, Bergerot P, et al.
Target Oncol. 2019 Dec;14(6):639-645.
DOI: 10.1007/s11523-019-00676-y.

Abstract

Until recently, a dichotomy existed in the front-line approach of metastatic clear-cell renal cell carcinoma (mRCC). Specifically, patients received either targeted therapy or immunotherapy. Targeted therapy entailed use of agents blocking signaling through the vascular endothelial growth factor (VEGF) receptor, such as cabozantinib, sunitinib, or pazopanib. Immunotherapy entailed dual therapy with nivolumab and ipilimumab, both checkpoint inhibitors for intermediate/poor International Metastatic RCC Database Consortium (IMDC)-risk disease patients. Within the past year, two datasets have emerged that led to recent approvals of combined therapy with VEGF and checkpoint inhibitors. These regimens (axitinib with either avelumab or pembolizumab) are among several that have been or will be evaluated for patients with newly diagnosed mRCC. We aim to facilitate treatment decisions through this comprehensive and contextualized overview of recent datasets in this therapeutic space.

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The impact of corticosteroid use during anti-PD1 treatment

Pan EY, Merl MY, Lin K.
J Oncol Pharm Pract. 2019 Sep 7.
DOI: 10.1177/1078155219872786.

Abstract

Background

The advent of anti-PD1 therapy for cancer treatment has led to improvements in response rates and overall survival. However, anti-PD1 therapy has the potential to cause immune-related adverse events (irAEs), which can be treated with corticosteroids if severe. The clinical implications of concomitant immunotherapy and systemic steroids remain unclear, as short courses of steroids do not significantly suppress T-cell function. The primary objective of this study is to determine if the use of concomitant steroids impacts the efficacy of anti-PD1 therapy.

Methods

This retrospective, single-center study reviewed adult patients who received at least four cycles of nivolumab or pembrolizumab for the treatment of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma from November 2014 to February 2016. Patients who received steroids (prednisone equivalent >10 mg) during anti-PD1 therapy were divided into two main cohorts based on the duration of steroid administration of ≤2 weeks or >2 weeks. Time to disease progression, overall response, and overall survival were assessed.

Results

The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile.

Conclusion

High-dose steroids for long durations during anti-PD1 therapy may be associated with poorer survival outcomes.

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Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study

Procopio G, Apollonio G, Cognetti F, et al.
Eur Urol Oncol. 2019 Nov;2(6):699-707
DOI: 10.1016/j.euo.2019.08.011

Abstract

Background

In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy.

Objective

To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radicalmetastasectomy in mRCC patients.

Design, setting, and participants

The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile.

Outcome measurements and statistical analysis

RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves.

Results and limitations

At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm.

Conclusions

This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy.

Patient summary

This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.

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