scholarly journals Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2849
Author(s):  
Emilio Esteban ◽  
Francisco Exposito ◽  
Guillermo Crespo ◽  
Julio Lambea ◽  
Alvaro Pinto ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Antiangiogenic Therapy ◽  
Prognostic Index ◽  
Serum Levels ◽  
Cox Regression Analysis ◽  
Tumor Expression

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p < 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.

Second-line VEGF TKI after IO combination therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 684-684
Author(s):  
Igor Stukalin ◽  
Shaan Dudani ◽  
Connor Wells ◽  
Chun Loo Gan ◽  
Sumanta K. Pal ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Response Rates ◽  
Second Line ◽  
First Line ◽  
Cox Regression Analysis

684 Background: Immuno-Oncology (IO) combinations are standard of care first-line treatment for metastatic renal cell carcinoma (mRCC). Data on therapy with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) post-progression on IO-combination therapy are limited. Methods: Using the IMDC, a retrospective analysis was done on mRCC patients treated with second-line VEGF TKIs after receiving IO combination therapy. Patients received first-line ipilimumab+nivolumab (IOIO) or anti-PD(L)1+anti-VEGF (IOVE). Baseline variables and second-line IMDC risk factors were collected. Overall response rates (ORR), time to treatment failure (TTF) and overall survival (OS) were determined. Multivariable Cox regression analysis was performed. Results: 142 patients were included. 75 patients received IOIO and 67 received IOVE pretreatment. The ORR of 2nd line therapy was 17/46 (37%) and 7/57 (12%) in the IOIO and IOVE pretreated groups, respectively (p<0.01). 2nd-line TTF was 5.4 months (95% CI 4.1-8.3) for the IOIO- and 4.6 months (95% CI 3.7-5.8) for the IOVE-pretreated group (p=0.37). 2nd-line median OS was 17.2 months (95% CI 10.8-35.1) and 11.8 months (95% CI 9.9-21.3) for the prior IOIO and IOVE groups, respectively (p=0.13). The hazard ratio adjusted by IMDC for IOVE vs IOIO pretreatment was 1.22 (95% CI 0.73-2.07, p=0.45) for 2nd line TTF and 1.43 (95% CI 0.74-2.8, p=0.29) for 2nd line OS. Conclusions: VEGF TKIs show activity after combination IO therapy. Response rates are higher in patients treated with VEGF TKIs after first-line IOIO compared to after IOVE. In patients with VEGF TKI after IOIO or IOVE, no difference in OS and TTF was observed.[Table: see text]

Checkpoint inhibitors in metastatic renal cell carcinoma patients including elderly subgroups: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4580-4580
Author(s):  
Steven Yip ◽  
Connor Wells ◽  
Raphael Brandao Moreira ◽  
Alex Wong ◽  
Sandy Srinivas ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Real World ◽  
Renal Cell ◽  
Cox Regression ◽  
Cell Cancer ◽  
Second Line ◽  
Cox Regression Analysis ◽  
Poor Risk

4580 Background: Immuno-oncology (IO) checkpoint inhibitor treatment outcomes are poorly characterized in the real world metastatic renal cell cancer (mRCC) patient population, including geriatric patients. Methods: Using the IMDC database, a retrospective analysis was performed on mRCC patients treated with IO, as listed below. Patients received one or more lines of IO therapy, with or without a targeted agent. Duration of treatment (DOT) and overall response rates (ORR) were calculated. Cox regression analysis was performed to examine the association between age as a continuous variable and DOT. Results: 312 mRCC patients treated with IO were included. In patients who were evaluable, ORR to IO therapy was 29% (32% first-, 22% second-, 33% third-, and 32% fourth-line treatment (Tx)). Patients treated with second-line IO therapy were divided into favorable, intermediate, and poor risk using IMDC criteria; the corresponding median DOT rates were not reached (NR), 8.6 mo, and 1.9 mo, respectively (p<0.0001). Based upon age, hazard ratios were calculated in the first- through fourth-line therapy setting, ranging from 1.03 to 0.97. Conclusions: The ORR to IO appears to remain consistent, regardless of line of therapy. In the second-line, IMDC criteria appear to appropriately stratify patients into favorable, intermediate, and poor risk groups for DOT. Premature OS data will be updated. In contrast to clinical trial data, longer DOT is observed in real world practice. Age may not be a factor influencing DOT. [Table: see text]

scholarly journals Real-world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium

2019 ◽  
Vol 26 (2) ◽  
Author(s):  
I. Stukalin ◽  
J. C. Wells ◽  
J. Graham ◽  
T. Yuasa ◽  
B. Beuselinck ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Real World ◽  
Renal Cell ◽  
Cox Regression ◽  
Kinase Inhibitor ◽  
Second Line ◽  
Cox Regression Analysis ◽  
Significant Difference

Objectives In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting.Methods Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan–Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment.Results The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35.Conclusions Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.

Cytoreductive nephrectomy in metastatic papillary renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 581-581 ◽  
Author(s):  
Jeffrey Graham ◽  
Connor Wells ◽  
Frede Donskov ◽  
Jae-Lyun Lee ◽  
Anna Paola Fraccon ◽  
...  
Keyword(s):  
Risk Factors ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Cytoreductive Nephrectomy ◽  
Cox Regression Analysis ◽  
Baseline Characteristics

581 Background: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC), but the role of CN in patients with papillary histology is unclear. Methods: Using the IMDC database, a retrospective analysis was performed on patients with papillary mRCC treated with or without CN. Baseline characteristics and IMDC risk factors were collected. Median overall survival (OS) was determined for both patient groups. Multivariable Cox regression analysis was performed to control for imbalances in individual IMDC risk factors. Results: In total, 353 patients with papillary mRCC with (n = 75) or without (n = 278) a component of clear cell histology were identified. Median follow-up time was 57.1 months (95% CI 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2 months (95% CI 12.0-16.1). Baseline characteristics are in Table 1 and patients who had CN were more likely to be younger, with better KPS, and have sarcomatoid histology. Median OS in patients with CN was 16.3 months (95% CI 13.1-19.2), compared to 8.6 months (95% CI 6.1-12.2; 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). Conclusions: The use of CN in patients with mRCC and papillary histology appears to be associated with improved survival when compared to no CN after adjustment for risk criteria. A clinical trial in this rare population may not be possible but this data does corroborate with clear cell literature. [Table: see text]

First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Preliminary results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 584-584 ◽  
Author(s):  
Shaan Dudani ◽  
Jeffrey Graham ◽  
Connor Wells ◽  
Sumanta K. Pal ◽  
Nazli Dizman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Combination Strategy ◽  
Cox Regression Analysis ◽  
Significant Difference ◽  
Baseline Characteristics

584 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L PD(L)1-VEGF (PV) inhibitor combinations. The efficacy of these two strategies has not been compared. Methods: Using the IMDC dataset, patients (pts) treated with any 1L PV combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 164 pts received 1L IO combination therapy: 104 treated with PV combinations and 60 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups (Table). When comparing PV combinations vs ipi-nivo, 1L response rates (RR) were 30% vs 39% (p = 0.29), time to treatment failure (TTF) was 13.2 (95% CI 8.3-16.1) vs 8.5 months (95% CI 5.7-14.0, p = 0.31), and median overall survival (OS) was not reached (NR) (95% CI 19.7-NR) vs NR (95% CI 27.6-NR, p = 0.39). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.77 (95% CI 0.44-1.35, p = 0.36) and the HR for death was 0.94 (95% CI 0.33-2.71, p = 0.91). Similar results were seen when restricting the cohort to IMDC intermediate/poor risk pts only. In pts receiving subsequent VEGF TKI monotherapy, second-line (2L) RR (13% vs 45%, p = 0.07) and TTF (5.5 vs 5.4 months, p = 0.80) for PV combinations (n = 15) vs ipi-nivo (n = 20) were not significantly different. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as PV combinations and ipi-nivo have comparable RR, TTF and OS. Although there is a trend towards differences in RR, there does not appear to be a significant difference in TTF for patients receiving 2L VEGF TKI therapy. [Table: see text]

The comparison of cytoreductive nephrectomy (CN) with tyrosine kinase inhibitor therapy alone in patients with primary metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 304-304
Author(s):  
Shingo Hatakeyama ◽  
Sei Naito ◽  
Kazuyuki Numakura ◽  
Renpei Kato ◽  
Tomoyuki Koguchi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Cytoreductive Nephrectomy ◽  
Ctrl Group ◽  
Cox Regression Analysis ◽  
Significant Difference

304 Background: We aimed to compare overall survival (OS) between patients with metastatic renal cell carcinoma (mRCC) treated by cytoreductive nephrectomy (CN) and those not treated by CN. Methods: We retrospectively evaluated 278 patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019. Patients were divided into two groups, CN group (immediate or deferred CN) and systemic TKI therapies alone without CN (Ctrl group). The OS was compared in all patients between the Ctrl and CN groups, between the Ctrl and immediate CN groups, between the Ctrl and deferred CN groups, and between the deferred CN and immediate CN groups. Analyses were weighted using the propensity score–based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. Results: The median age of the patients was 65 (range 59–73) years. Of the 278 patients, 132 and 146 were in the Ctrl and CN (immediate: 107 and deferred: 39) groups, respectively. A significant difference was noted between the Ctrl and CN groups in age, clinical stage, IMDC risk factors, and the number of metastatic sites. An IPTW-adjusted Cox regression analysis revealed a significant difference in OS between the Ctrl and CN groups and between the Ctrl and immediate or deferred CN groups. However, there was no significant difference in OS between immediate and deferred CN groups. Conclusions: The OS in CN group was significantly longer than that in Ctrl group even after the adjustment of potential selection biases.

Interleukin-4 Promoter Polymorphisms: A Genetic Prognostic Factor for Survival in Metastatic Renal Cell Carcinoma

2007 ◽  
Vol 25 (7) ◽  
pp. 845-851 ◽  
Author(s):  
Thomas Kleinrath ◽  
Christoph Gassner ◽  
Peter Lackner ◽  
Martin Thurnher ◽  
Reinhold Ramoner
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clinical Course ◽  
Prognostic Significance ◽  
Interleukin 4 ◽  
Promoter Polymorphisms ◽  
Cox Regression Analysis ◽  
Metastatic Rcc

Purpose Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance. Patients and Methods A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors. Results Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype −589T−33T/−589C−33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype −589T−33T and −589C−33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype −589T−33T (P < .01) and an increase of IL4 haplotype −589C−33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype −589T−33T and −589C−33C (3.78 months) compared with patients homozygote for IL4 haplotype −589C−33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected. Conclusion Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.

Primary Apoptosis as a Prognostic Index for the Classification of Metastatic Renal Cell Carcinoma

2002 ◽  
Vol 168 (2) ◽  
pp. 460-464 ◽  
Author(s):  
E.N. Richter ◽  
K. Oevermann ◽  
N. Buentig ◽  
S. Störkel ◽  
I. Dallmann ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Prognostic Index

Can Systemic Immune-Inflammation Index Create a New Perspective for the IMDC Scoring System in Patients with Metastatic Renal Cell Carcinoma?

2021 ◽  
pp. 1-8
Author(s):  
Fatma Bugdayci Basal ◽  
Cengiz Karacin ◽  
Irem Bilgetekin ◽  
Omur Berna Oksuzoglu
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factor ◽  
Regression Model ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Independent Prognostic Factor ◽  
Cox Regression Model ◽  
Kaplan Meier

Introduction: The aim of the study was to evaluate impact of the systemic immune-inflammation index (SII) on prognosis and survival within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score groups. Methods: The records of 187 patients with metastatic renal cell carcinoma (RCC) were reviewed retrospectively. The SII was calculated as follows: SII = Neutrophil × Platelet/Lymphocyte. The patients were categorized into 2 groups based on a median SII of 730 (×109 per 1 L) as SII low (<730) and SII high (≥730). The Kaplan-Meier method was used for survival analysis and a Cox regression model was utilized to determine independent predictors of survival. Results: The median age was 61 years (range: 34–86 years). Kaplan-Meier tests revealed significant differences in survival between the SII-low and SII-high levels (27.0 vs. 12.0 months, respectively, p < 0.001). The Cox regression model revealed that SII was an independent prognostic factor. The implementation of the log-rank test in the IMDC groups according to the SII level provided the distinction of survival in the favorable group (SII low 49.0 months vs. SII high 11.0 months, p < 0.001), in the intermediate group (SII low 26.0 vs. SII high 15.0 months, p = 0.007), and in the poor group (SII low 19.0 vs. SII high 6.0 months, p = 0.019). Conclusion: The SII was an independent prognostic factor and provided significant differences in survival for the favorable, intermediate, and poor IMDC groups. Thus, the SII added to the IMDC score may be clinically beneficial in predicting survival.

A consensus prognostic factor model for survival in patients with metastatic renal cell carcinoma: A Kidney Cancer Association’s International Kidney Cancer Working Group (IKCWG) study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5109-5109 ◽  
Author(s):  
P. Royston ◽  
J. Bacik ◽  
P. Elson ◽  
J. B. Manola ◽  
M. Mazumdar
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Kidney Cancer ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Multivariable Analysis ◽  
Prognostic Index ◽  
The United States ◽  
Model Complexity

5109 Background: Numerous well-designed retrospective studies of prognostic factors (pf) for survival (S) in metastatic renal cell carcinoma (mRCC) patients (pts) have been conducted since 1986. However, no single model for describing S in this population has been universally accepted. Methods: Authors of several existing prognostic indices, and others, formed the IKCWG to develop a single validated S model. The IKCWG has established a comprehensive database of previously reported clinical pf from 3748 previously untreated mRCC pts entered on institution review board approved clinical trials conducted by 11 centers in Europe and the United States from 1975–2002. Results: Median age at study entry was 58, 70% of pts were male, 89% had ECOG performance status (PS) 0 or 1; 75% had prior nephrectomy. 72%, 30%, and 19% of pts had lung, bone, and liver metastases (mets), respectively. 72% received interferon-a and/or interleukin-2 based treatments (tx); 25% were txd with chemotherapy/hormones only; 3% received other tx. 88% of pts have died; median S was 11.1 months (m). All examined factors except sex, age, and histology impacted S at p<.001 in univariable analysis. Multivariable analysis using a log-logistic model stratified by center and multivariable fractional polynomials was performed to identify independent predictors of S. Missing data were handled using multiple imputation methods. Using p=.0044 as the criterion for variable selection to avoid overly complex models, a model comprising tx, PS, number of met sites, interval from diagnosis to tx, and pre-tx hemoglobin, WBC, LDH, alkaline phosphatase and calcium was identified. The 25th and 75th percentiles of the prognostic index formed by multiplying each factor by its regression coefficient were used as cutpoints to form three risk (r) groups with median S times (SE) of: favorable r (n=937; 27.8 (0.4) m), intermediate r (n=1874; 11.4 (0.2) m), and poor r (n=937; 4.1 (0.1) m). Conclusions: 9 clinical factors can be used to model S in mRCC and form 3 distinct prognostic groups. Additional model building to determine if model complexity can be reduced further, validation in independent data and comparison to existing prognostic models are underway. No significant financial relationships to disclose.

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