scholarly journals Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial

2020 ◽  
Vol 38 (34) ◽  
pp. 4064-4075
Author(s):  
Tim Eisen ◽  
Eleni Frangou ◽  
Bhavna Oza ◽  
Alastair W.S. Ritchie ◽  
Benjamin Smith ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Outcome Analysis ◽  
Double Blind ◽  
Risk Of Recurrence

PURPOSE SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

scholarly journals Predictive Ability for Disease-Free Survival of the GRade, Age, Nodes, and Tumor (GRANT) Score in Patients with Resected Renal Cell Carcinoma

2020 ◽  
Vol 14 (2) ◽  
pp. 98-104
Author(s):  
Alessio Cortellini ◽  
Sebastiano Buti ◽  
Melissa Bersanelli ◽  
Katia Cannita ◽  
Giada Pinterpe ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Multivariate Analysis ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Free Survival ◽  
Risk Of Recurrence ◽  
Significant Difference ◽  
Disease Free

Background: Recently, the GRANT (GRade, Age, Nodes, and Tumor) score was validated through an adjuvant trial population. Methods: This retrospective study evaluated the performance of the GRANT score as a prognostic model for disease-free survival (DFS), compared to the University of California Los Angeles Integrated Staging System (UISS) score, in a “real-life” population of early renal cell carcinoma patients. A uni-/multivariate analysis of DFS was also performed, to weigh the roles of baseline clinical factors. Results: From February 1998 to January 2018, 134 consecutive patients were enrolled, of which 85 patients (63.4%) had a favorable GRANT score, 49 (36.6%) an unfavorable GRANT score, and 21 (15.7%), 84 (62.6%), and 29 (21.6%) patients had a low, intermediate, or high risk of recurrence according to the UISS score, respectively. The median follow-up was 96 months. The median DFS of the overall study population was 53.7 months (95% CI: 38.4-87.8). Only bilateral renal cell carcinoma (p = 0.0041), Fuhrman grade 3/4 (p = 0.0008), pT3b- 4 (p = 0.0324), and pN1-2 (p = 0.0303) pathological status were confirmed as independent predictors of a shorter DFS by the multivariate analysis. The median DFS of patients with favorable and unfavorable GRANT scores were 84.9 (95% CI: 49.8-129) and 38.4 months (95% CI: 24.4-87.8), respectively, with a statistically significant difference (p = 0.0147). The median DFS of patients with low, intermediate, and high risk of recurrence according to the UISS score were 92.3 (95% CI: 18.1-153.9), 51.7 (95% CI: 36.2-87.8), and 49.8 months (95% CI: 31.3-129), respectively, without statistically significant differences (p = 0.4728). DFS c-statistic values were 0.59 (95% CI: 0.51-0.67) and 0.51 (95% CI: 0.42-0.60) for the GRANT and the UISS scores, respectively. Conclusion: The GRANT score might be a useful tool that is user-friendly and easy to perform in clinical practice.

scholarly journals Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: Exploratory pharmacogenomic analysis.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 576-576 ◽  
Author(s):  
Daniel J. George ◽  
Jean-Francois Martini ◽  
Michael D. Staehler ◽  
Yen-Hwa Chang ◽  
Jan Breza ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Statistical Tests ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Nucleotide Polymorphisms ◽  
Comparison Results

576 Background: In the phase III S-TRAC trial, adjuvant sunitinib (SU) prolonged disease-free survival (DFS) vs placebo (PBO) in patients with locoregional renal cell carcinoma at high risk of recurrence after nephrectomy (median 6.8 vs 5.6 y; hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59–0.98; P= 0.03). An exploratory analysis evaluated associations between single nucleotide polymorphisms (SNPs) in angiogenesis-related genes and clinical outcomes in S-TRAC. Methods: Prospectively collected blood samples were genotyped for 10 SNPs and 1 insertion/deletion mutation with TaqMan assays. DFS was compared with a log-rank test for each SNP genotype in SU vs PBO arms and between SNP genotypes within each arm. P-values are unadjusted for multiplicity comparison. Results: Of 615 patients, 286 (142 SU; 144 PBO) were analyzed. There were generally no genotype frequency deviations from the Hardy-Weinberg equilibrium, but linkage disequilibrium was seen between VEGFA rs699947 and rs833061 on chromosome 6 (D′ = 1.000, r2 = 0.979). Longer DFS was observed with SU vs PBO for VEGFR1 rs9554320 C/C (median: not reached [NR] vs 5.56 y; HR 0.44, 95% CI 0.21–0.91; P= 0.023), VEGFR2 rs2071559 T/T (median: NR vs 4.47 y; HR 0.46, 95% CI 0.23–0.90; P= 0.020), and eNOS rs2070744 T/T (median: 7.07 vs 3.44 y; HR 0.53, 95% CI 0.30–0.94; P= 0.028), with a trend for VEGFR1 rs9582036 A/A (median: NR in both arms; P= 0.054) and SH3GL2 rs10963287 C/T (median: NR vs 5.35 y; P= 0.088). Shorter DFS was observed for VEGFR1 rs9582036 C/A vs C/C in the SU, PBO, and combined arms ( P< 0.05); for A/A vs common, the association was only seen in the SU arm ( P= 0.022). VEGFR1 rs9554320 A/C was associated with shorter DFS vs A/A in the PBO ( P= 0.038) and combined arm ( P= 0.006), with a trend in the SU arm ( P= 0.051). VEGFR2 rs1870377 T/T was associated with longer DFS vs A/A in the combined arms, but not in the PBO arm (n = 7 with A/A genotype in the SU arm precluded statistical tests). Conclusions: Correlations between common VEGFR1 and VEGFR2 SNPs and longer DFS with SU suggest germline SNPs are predictive of improved outcomes with adjuvant SU. Due to the exploratory nature of this analysis, prospective validation studies are needed to confirm these findings. Clinical trial information: NCT00375674.

scholarly journals Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study

2018 ◽  
Vol 24 (7) ◽  
pp. 1554-1561 ◽  
Author(s):  
Daniel J. George ◽  
Jean-François Martini ◽  
Michael Staehler ◽  
Robert J. Motzer ◽  
Ahmed Magheli ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Immune Biomarkers ◽  
Disease Free

RENAVIV: A randomized phase III, double-blind, placebo-controlled study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS681-TPS681 ◽  
Author(s):  
Rahul Raj Aggarwal ◽  
Scott Thomas ◽  
Ralph J. Hauke ◽  
Luke T. Nordquist ◽  
Pamela N. Munster
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Histone Acetylation ◽  
Renal Cell ◽  
Clear Cell ◽  
Locally Advanced ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo

TPS681 Background: Abexinostat is a pan-histone deacetylase (HDAC) inhibitor that has shown promising activity in prior pre-clinical studies and early phase clinical trials. A phase 1b study of pazopanib plus abexinostat (Aggarwal et al. J Clin Oncol 2017) demonstrated strikingly durable responses in patients (pts) with clear cell renal cell carcinoma (RCC), including one patient with previously refractory disease with ongoing response for > 5 years’ duration. Induction of histone acetylation in peripheral blood mononuclear cells (PBMCs) was associated with durable treatment response. We hypothesize that the addition of abexinostat to pazopanib will significantly improve outcomes in patients with clear cell RCC. Methods: RENAVIV is a global, randomized, double-blind, placebo-controlled, two arm phase 3 study of pazopanib plus abexinostat versus pazopanib plus placebo, in pts with locally advanced or metastatic RCC with clear cell component. Up to one prior line of immunotherapy is allowed. Prior VEGF-targeting tyrosine kinase inhibitor treatment is prohibited. Stratification factors include: 1) Prior immunotherapy (yes/no) and 2) prognostic group (good, intermediate, poor). Pts randomized to pazopanib + placebo have the option of crossing over to receive pazopanib plus abexinostat at the time of disease progression. The primary endpoint is PFS by independent review committee. Secondary endpoints include PFS by investigator assessment, overall survival, safety, objective response rate (ORR), duration of response, patient-reported quality of life, and outcomes in cross-over population. Planned correlative studies include association between histone acetylation and HDAC expression in PBMCs with clinical outcomes. The total planned accrual is 413 pts, estimated to provide 90% power to detect a hazard ratio of 0.67 in the comparison of PFS between experimental versus control arms, with an overall two-sided type I error rate of 0.025. A pre-specified minimum of 50% of patients are required to have received prior immunotherapy. The first patient was enrolled in October 2018. Clinical trial information: NCT03592472.

Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial

2003 ◽  
Vol 21 (16) ◽  
pp. 3133-3140 ◽  
Author(s):  
Joseph I. Clark ◽  
Michael B. Atkins ◽  
Walter J. Urba ◽  
Steven Creech ◽  
Robert A. Figlin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Locally Advanced ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Group Randomized Trial

Purpose: This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). Patients and Methods: Eligibility requirements were resected locally advanced (LA; T3b-4 or N1–3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. Results: Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P = .73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P = .38). Analysis including metastasectomy patients made no difference in DFS or overall survival. Conclusion: One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.

scholarly journals Bioinformatics analysis of C3 and CXCR4 demonstrates their potential as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jing Quan ◽  
Yuchen Bai ◽  
Yunbei Yang ◽  
Er Lei Han ◽  
Hong Bai ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Therapeutic Targets ◽  
Disease Free Survival ◽  
Prognostic Biomarkers ◽  
Hub Genes ◽  
Cell Renal Cell Carcinoma ◽  
Upregulated Genes

Abstract Background The molecular prognostic biomarkers of clear cell renal cell carcinoma (ccRCC) are still unknown. We aimed at researching the candidate biomarkers and potential therapeutic targets of ccRCC. Methods Three ccRCC expression microarray datasets (include GSE14762, GSE66270 and GSE53757) were downloaded from the gene expression omnibus (GEO) database. The differentially expressed genes (DEGs) between ccRCC and normal tissues were explored. The potential functions of identified DEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). And then the protein - protein interaction network (PPI) was established to screen the hub genes. After that, the expressions of hub genes were identified by the oncomine database. The hub genes’ prognostic values of patients with ccRCC were analyzed by GEPIA database. Results A total of 137 DEGs were identified by utilizing the limma package and RRA method, including 63 upregulated genes and 74 downregulated genes. It is found that 137 DEGs were mainly enriched in 82 functional terms and 24 pathways in accordance with the research results. Thirteen highest-scoring genes were screened as hub genes (include 10 upregulated genes and 3 downregulated candidate genes) by utilizing the PPI network and module analysis. Through integrating the oncoming database and GEPIA database, the author found that C3 and CXCR4 are not only overexpressed in ccRCC, but also associated with the prognosis of ccRCC. Further results could reveal that patients with high C3 expression had a poor overall survival (OS), while patients with high CTSS and TLR3 expressions had a good OS; patients with high C3 and CXCR4 expressions had a poor disease-free survival (DFS), while ccRCC patients with high TLR3 expression had a good DFS. Conclusion These findings suggested that C3 and CXCR4 were the candidate biomarkers and potential therapeutic targets of ccRCC patients.

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