Articles

Tivozanib in renal cell carcinoma: a new approach to previously treated disease

Salgia NJ , Zengin ZB, Pal SK.
Ther Adv Med Oncol. 2020 May 22;12:1758835920923818.
DOI: 10.1177/1758835920923818

Abstract

Targeted therapies have been a mainstay of the renal cell carcinoma (RCC) treatment paradigm for the better part of two decades. Multikinase inhibitors of the vascular endothelial growth factor receptor tyrosine kinases (VEGF-TKIs) comprise nearly all targeted therapies in RCC, having been prospectively tested through large, multi-institutional phase III trials. Tivozanib is a VEGF-TKI with high selectivity for VEGF receptors 1–3. Tivozanib has been under investigation for nearly 15 years, with a robust portfolio of preclinical and clinical data. This review seeks to characterize tivozanib within the context of RCC by highlighting preclinical and early clinical trials alongside the phase III trials in RCC, TIVO-1, and TIVO-3. We also aim to explore further trials of tivozanib, whether in combination with other agents and/or in differing disease settings, while providing insight into the utility of tivozanib as a clinical tool for the management of RCC.

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Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor of Disease-free Survival in Postnephrectomy High-risk Locoregional Renal Cell Carcinoma: Analysis of the S-TRAC Trial

Patel A, Ravaud A, Motzer RJ, et al.
Clin Cancer Res 2020 Jun 16.
DOI: 10.1158/1078-0432.CCR-20-0704

Abstract

Purpose

In the S-TRAC trial, adjuvant sunitinib improved disease-free survival (DFS) compared with placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence. This post hoc exploratory analysis investigated the neutrophil-to-lymphocyte ratio (NLR) for predictive and prognostic significance in the RCC adjuvant setting.

Experimental design

Kaplan-Meier estimates and Cox proportional analyses were performed on baseline NLR and change from baseline at week 4 to assess their association with DFS. Univariate P values were two-sided and based on an unstratified log-rank test.

Results

609 of 615 patients had baseline NLR values; 574 patients had baseline and week 4 values. Sunitinib-treated patients with baseline NLR <3 had longer DFS versus placebo (7.1 vs. 4.7; HR, 0.71; P = 0.02). For baseline NLR ≥3, DFS was similar regardless of treatment (sunitinib 6.8 vs. placebo not reached; HR, 1.03; P = 0.91). A ≥25% NLR decrease at week 4 was associated with longer DFS versus no change (6.8 vs. 5.3 years; HR, 0.71; P = 0.01). A greater proportion of sunitinib-treated patients had ≥25% NLR decrease at week 4 (71.2%) versus placebo (17.4%). Patients with ≥25% NLR decrease at week 4 received a higher median cumulative sunitinib dose (10,137.5 mg) versus no change (8,168.8 mg) or ≥25% increase (6,712.5 mg).

Conclusions

In the postnephrectomy high-risk RCC patient cohort, low baseline NLR may help identify those most suitable for adjuvant sunitinib. A ≥25% NLR decrease at week 4 may be an early indicator of those most likely to tolerate treatment and derive DFS benefit.

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Compensatory Changes in Parenchymal Mass and Function after Radical Nephrectomy

Palacios D, Caraballo E, Tanaka H, et al.
J Urol 2020 Jul;204(1):42-49
DOI: 10.1097/JU.0000000000000797

Abstract

Purpose

Loss of renal function remains a major limitation of radical nephrectomy. The extent of renal functional compensation by the preserved kidney after radical nephrectomy has not been adequately studied in this elderly population with comorbidities.

Materials and Methods

A total of 273 patients treated with radical nephrectomy without end stage renal disease with available preoperative nuclear renal scans were included in the analysis. Renal functional compensation was defined as percent change in estimated glomerular filtration rate of the preserved kidney after radical nephrectomy. Estimated glomerular filtration rate was calculated by the Chronic Kidney Disease-Epidemiology Collaboration formula up to 5 years postoperatively. Preoperative/postoperative parenchymal volumes of the preserved kidney were measured from cross-sectional imaging. Multiple regression was used to identify predictive factors for renal functional compensation.

Results

Median age was 67 years and 67% of the patients were male. Overall 70% had hypertension, 26% diabetes and 37% preexisting chronic kidney disease. Locally advanced (T3a or greater) tumors were found in 53% of cases. Renal functional compensation was observed at 2 weeks (median 10%) and increased during the first 3 months (median 26%) after radical nephrectomy. Functional stability was then observed to 5 years. Renal parenchymal volume increased a median of 10% at 3 to 12 months but in addition, the functional efficiency per unit of parenchymal volume also increased 8% (estimated glomerular filtration rate units/cm3 of parenchyma was 0.236 postoperatively vs 0.208 preoperatively, p=0.004). Age (-0.85, p <0.01), global preoperative estimated glomerular filtration rate (-0.28, p <0.01) and split renal function of the removed kidney (0.61, p <0.01) were independent predictors of renal functional compensation.

Conclusions

Percent renal functional compensation after radical nephrectomy is greater in younger patients, when preoperative estimated glomerular filtration rate is lower and when the removed kidney has more robust function. Increases in measurable parenchymal mass and functional efficiency contribute substantially to renal functional compensation.

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Prognostic Value of Histologic Subtype and Treatment Modality for T1a Kidney Cancers

Siev M, Renson A, Tan H, et al
Kidney Cancer, vol. 4, no. 1, pp. 49-58, 2020
DOI: 10.3233/KCA-190072

Abstract

Introduction

To evaluate overall survival (OS) of T1a kidney cancers stratified by histologic subtype and curative treatment including partial nephrectomy (PN), percutaneous ablation (PA), and radical nephrectomy (RN).

Materials and Methods

We queried the National Cancer Data Base (2004–2015) for patients with T1a kidney cancers who were treated surgically. OS was estimated by Kaplan-Meier curves based on histologic subtype and management. Cox proportional regression models were used to determine whether histologic subtypes and management procedure predicted OS.

Results

46,014 T1a kidney cancers met inclusion criteria. Kaplan Meier curves demonstrated differences in OS by treatment for clear cell, papillary, chromophobe, and cystic histologic subtypes (all p < 0.001), but no differences for sarcomatoid (p = 0.110) or collecting duct (p = 0.392) were observed. Adjusted Cox regression showed worse OS for PA than PN among patients with clear cell (HR 1.58, 95% CI [1.44–1.73], papillary RCC (1.53 [1.34–1.75]), and chromophobe RCC (2.19 [1.64–2.91]). OS was worse for RN than PN for clear cell (HR 1.38 [1.28–1.50]) papillary (1.34 [1.16–1.56]) and chromophobe RCC (1.92 [1.43–2.58]). Predictive models using Cox proportional hazards incorporating histology and surgical procedure alone were limited (c-index 0.63) while adding demographics demonstrated fair predictive power for OS (c-index 0.73).

Conclusions

In patients with pathologic T1a RCC, patterns of OS differed by surgery and histologic subtype. Patients receiving PN appears to have better prognosis than both PA and RN. However, the incorporation of histologic subtype and treatment modality into a risk stratification model to predict OS had limited utility compared with variables representing competing risks.

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Electrocoagulation with greased lidocaine gel 2% as hemostatic maneuver after minimally invasive partial nephrectomy: Experimental and preliminary clinical results

Panico V, Simardi L, Faria E, et al.
Arch Cancer Sci Ther. 2020
DOI: 10.29328/journal.acst.1001017

Abstract

Methods

Experimental phase: Performed a partial nephrectomy off clamp in pig model followed by cauterization of lidocaine gel 2% with different power (control, 30W, 50W and 100W) in the kidney resection bed to evaluate efficacy and deep injury extension.

Clinical phase

20 patients submitted to laparoscopic or partial nephrectomy for low risk RENAL score were utilized greased lidocaine gel 2% with 50W in cautery scalpel to hemostasis of renal parenchima to validate efficacy and safety.

Results

Experimental study shows that this technique is effective and promote better hemostasis with 50W and 100W, with deep injury of less than 3 mm. Clinical study confirm efficacy, good control of hemorrage, few complications and no transfusion. Minimal changes in hematocrit, haemoglobin and creatinine were observed.

Conclusions

In this preliminary experience the use of this new alternative to hemostasis for low risk partial nephrectomy was satisfactory and with good intra and postoperative results. The best advantages were safety in terms of the depth thermal injury, low cost and absence of artifacts over the resection area observed at CT scan postoperatively.

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Construction of a novel gene-based model for prognosis prediction of clear cell renal cell carcinoma

Zhang, Z., Lin, E., Zhuang, H. et al.
Cancer Cell Int 20, 27 (2020).
DOI: 10.1186/s12935-020-1113-6

Abstract

Background

Clear cell renal cell carcinoma (ccRCC) comprises the majority of kidney cancer death worldwide, whose incidence and mortality are not promising. Identifying ideal biomarkers to construct a more accurate prognostic model than conventional clinical parameters is crucial.

Methods

Raw count of RNA-sequencing data and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA). Tumor samples were divided into two sets. Differentially expressed genes (DEGs) were screened in the whole set and prognosis-related genes were identified from the training set. Their common genes were used in LASSO and best subset regression which were performed to identify the best prognostic 5 genes. The gene-based risk score was developed based on the Cox coefficient of the individual gene. Time-dependent receiver operating characteristic (ROC) and Kaplan–Meier (KM) survival analysis were used to assess its prognostic power. GSE29609 dataset from GEO (Gene Expression Omnibus) database was used to validate the signature. Univariate and multivariate Cox regression were performed to screen independent prognostic parameters to construct a nomogram. The predictive power of the nomogram was revealed by time-dependent ROC curves and the calibration plot and verified in the validation set. Finally, Functional enrichment analysis of DEGs and 5 novel genes were performed to suggest the potential biological pathways.

Results

PADI1, ATP6V0D2, DPP6, C9orf135 and PLG were screened to be significantly related to the prognosis of ccRCC patients. The risk score effectively stratified the patients into high-risk group with poor overall survival (OS) based on survival analysis. AJCC-stage, age, recurrence and risk score were regarded as independent prognostic parameters by Cox regression analysis and were used to construct a nomogram. Time-dependent ROC curves showed the nomogram performed best in 1-, 3- and 5-year survival predictions compared with AJCC-stage and risk score in validation sets. The calibration plot showed good agreement of the nomogram between predicted and observed outcomes. Functional enrichment analysis suggested several enriched biological pathways related to cancer.

Conclusions

In our study, we constructed a gene-based model integrating clinical prognostic parameters to predict prognosis of ccRCC well, which might provide a reliable prognosis assessment tool for clinician and aid treatment decision-making in the clinic.

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Female Gender Predicts Favorable Prognosis in Patients With Non-metastatic Clear Cell Renal Cell Carcinoma Undergoing Curative Surgery: Results From the International Marker Consortium for Renal Cancer (INMARC)

Fukushima H, Saito K, Yasuda Y, et al
Clinical Genitourinary Cancer, Vol 18, Issue 2, P111-116.E1, April 2020
DOI: 10.1016/j.clgc.2019.10.027

Abstract

Background

There is no clear consensus regarding gender differences in the prognosis of patients with clear-cell renal cell carcinoma (ccRCC). In the present study, we investigated the prognostic value of gender in patients with non-metastatic ccRCC undergoing curative surgery using the inverse probability of treatment weighting (IPTW) method to balance the difference in baseline factors between females and males.

Patients and Methods

We retrospectively reviewed the International Marker Consortium for Renal Cancer (INMARC) dataset and included 2055 patients with cT1-4N0M0 ccRCC who underwent partial or radical nephrectomy. The IPTW method was used to adjust for baseline characteristics between females and males (age, race, surgery type, and pT stage), and the association of gender with recurrence-free survival (RFS) was evaluated.

Results

During the follow-up (median, 30 months), 162 (8%) patients had disease recurrence (5-year RFS rate, 88%). Female gender (n = 712; 35%) was significantly associated with a lower Fuhrman grade (unweighted, P = .022; IPTW-weighted, P < .001). Females had significantly better RFS compared with males (unweighted, 5-year RFS rate, 92% vs. 87%; P = .005; IPTW-weighted, 5-year RFS rate, 92% vs. 86%; P = .002). IPTW-weighted multivariate analysis showed that female gender was an independent predictor for better RFS (hazard ratio, 0.59; P = .005) along with lower pT stage and lower Fuhrman grade. The prognostic significance of female gender was also observed in the unweighted multivariate analysis.

Conclusions

Female gender was significantly associated with a lower Fuhrman grade and better prognosis for patients with non-metastatic ccRCC undergoing curative surgery.

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Deferred Cytoreductive Nephrectomy Following Presurgical Vascular Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A Pooled Analysis of Prospective Trial Data

de Bruijn, Roderick et al.
European Urology Oncology, Volume 3, Issue 2, 168 – 173
DOI: 10.1016/j.euo.2019.12.004

Abstract

Background

Cancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting.

Objective

The aim of this study was to compare outcome in patients treated with presurgical VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI (upfront CN).

Design, setting, and participants

Pooled data from prospective trials in which a strategy of deferred CN in the absence of disease progression was investigated were compared with a retrospective dataset of upfront CN.

Outcome measurements and statistical analysis

Overall survival (OS) in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group.

Results and limitations

Patients were treated between 2006 and 2016. In the MSKCC intermediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo (95% confidence interval [CI] 25.0–51.0) compared with 22.8 mo (95% CI 17.9–30.6) after upfront CN (hazard ratio 0.72 [95% CI 0.52–0.996], p = 0.047). This study is limited by retrospective comparison of data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort.

Conclusions

In MSKCC intermediate-risk patients, a strategy of deferred CN in the absence of progression yields OS, which compares favourably with upfront CN and published trial data from CARMENA. This warrants a formal individual patient data analysis of CARMENA, SURTIME, and single-arm prospective studies to define the role and timing of deferred CN in intermediate-risk patients.

Patient summary

In this study, we report outcomes in patients with metastatic renal cell cancer treated with targeted therapy followed by nephrectomy, which compared favourably with nephrectomy followed by targeted therapy and results from published studies.

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Immunotherapy-based combinations versus standard first-line treatment for metastatic clear cell renal cell carcinoma: a systematic review and meta-analysis

Buti, S., Petrelli, F., Ghidini, A. et al.
Clin Transl Oncol (2020).
DOI: 10.1007/s12094-020-02292-z

Abstract

Purpose

Considering the recent publication of the results of several clinical trials for metastatic clear cell renal cell carcinoma (mRCC), we performed a systematic review and meta-analysis of randomized studies comparing standard first-line VEGFR-targeted therapy to immune checkpoint inhibitors-based combinations for mRCC patients.

Methods

3960 patients from 5 randomized clinical trials where available for evaluation.

Results

In the all-comers population, immunotherapy-based combinations were able to decrease the risk of death over the standard of care by 26% (HR 0.74; 95% CI 0.60–0.92; p = 0.006), to decrease the risk of progression by 21% (HR 0.79; 95% CI 0.72–0.86; p < 0.00001), and to increase the relative risk of response by 40% (HR 1.40; 95% CI 1.11–1.77; p = 0.006). For poor/intermediate-risk patients, the risk of death is decreased by 41% and the risk of progression by 27%.

Conclusion

The benefit of immunotherapy-based combinations in mRCC patients is independent from the IMDC risk group, but it is stronger for poor/intermediate-risk patients.

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