Outcomes Of mRCC Patients Research Articles

Beyond metastatic renal cell carcinoma (mRCC) clinical trials: Targeted therapy use and overall survival in community oncology clinics.

e15061 Background: Targeted therapies are now the standard of care for mRCC with use and expected outcomes defined by clinical trials. What are "real world" patterns of use and survival outcomes in mRCC patients (pts) treated in community oncology (COMM) settings? Methods: We reviewed a retrospective registry of adult mRCC pts from 11 COMM oncology practices, diagnosed since 1/2007 and not enrolled in a trial. Demographics, disease characteristics, treatment patterns and outcomes were recorded from the EMR and supplemented with chart abstraction.Pts were grouped by treatment sequence reflecting up to 3 exposures based on drug mechanism of action (VEGFR TKI [TKI] or mTOR inhibitor [mTOR]). Other pts received a non-TKI, non-mTOR therapy in the 1st three exposures (e.g., bevacizumab, cytokines, combinations, etc.). No Therapy pts received no systemic therapy as of data analysis. Survival analyses included Kaplan-Meier methods and Cox regression. Results: 255 patient/disease characteristics included: age 65±11 yrs; 68% male; 71% Caucasian; 62% clear cell histology (25% unknown); 1.6 ±0.9 metastatic sites. MSKCC risk was: 28% good, 63% intermediate, 10% poor. Median overall survival (OS) was 12.1 mo (95% CI: 8.7-15.4); median OS by sequence was: No Therapy (n=38; 3.7), mTOR (n=28; 5.2), TKI (n=79; 8.7), mTOR/TKI (n=10; 9.3), TKI/mTOR (n=32; 13.7), TKI/TKI (n=24; 20.7), Other (n=20; 22.5), TKI/mTOR/TKI (N=14; 29.8), TKI/TKI/mTOR (N=10; 33.1). Cox regression identified subgroups with differential outcomes. After significant covariates were controlled, compared with No Therapy, all regimens with TKI as 1st exposure had hazard ratios (HR) <1.0 (range=0.14 – 0.51; all p values ≤ 0.02). Other treatment had HR=0.31 (P=0.001), but when mTOR was the only treatment HR=1.04 (p=0.88). MSKCC scores of intermediate (HR=2.4) or poor (HR=4.5) were a significant risk (p<0.001). Conclusions: Only pts treated with two TKI exposures (≥20.7 mo) approached the best OS seen in trials (26 mo). For mTOR only, 1st line treatment in sicker patients, OS (5.2 mo) was shorter than trials (11 mo). Outcome differences between trial and community practice settings offer insights into opportunities to optimize care.

The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFR) polymorphisms in the prediction of clinical outcome for advanced renal cell carcinoma patients receiving first-line sunitinib.

e15074 Background: metastatic renal cell carcinoma (mRCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic strongholds are TKIs directed against the VEGF family (sunitinib and sorafenib). The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms, in determining the clinical outcome of mRCC patients receiving first-line sunitinib Methods: 41 histologic samples (biopsies and surgical specimens) of mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients progression free survival (PFS) and overall survival (OS) were analyzed for first line treatment. Results: VEGF A rs833061 C>T polymorphism was statistically significant in PFS (17 months for C vs 4 months for T; P = 0,0029) and OS (35,93 months for C vs 11 months for T; P = 0,0267). VEGF A rs699947 A>C was statistically significant for PFS (17 months for A vs 3,97 months for C; P = 0,0023) and OS (35,93 months for A vs 10,98 for C; P = 0,0272). VEGF A rs2010963 G>C was significant in PFS (16,98 months for G vs 4,65 for G/C vs 2,73 for C; P = 0,0188). VEGR3 rs6877011 C>G was significant in PFS (8,22 months for C vs 2,22 for C/G; P = 0,0361) and OS (35,93 months for C vs 12,08 for C/G; P = 0,0183). Conclusions: in our analysis patients with C polymorphism of rc833061, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line. These polymorphisms of the VEGF-A gene are probably connected with a better control of the neoangiogenesis process during TKIs therapy, maybe leading to vasculature normalization. Patients with C polymorphism of rs6877011 and G polymorphism of rs307822 seem equally to have a favourable impact in first line therapy. VEGFR-3 role is still matter of debate but seems to be involved in vessels sprouting and architecture.

The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) polymorphisms in the prediction of clinical outcome for patients with advanced renal cell carcinoma receiving first-line sunitinib.

380 Background: Metastatic renal cell carcinoma (mRCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic strongholds are TKIs directed against the VEGF family. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms, in determining the clinical outcome of mRCC patients receiving first-line sunitinib. Methods: 41 histologic samples (biopsies and surgical specimens) of mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients progression free survival (PFS) and overall survival (OS) were analyzed for first line treatment. Results: VEGF AIV rs833061 C>T polymorphism was statistically significant in PFS (17 months for C vs 4 months for T; P = 0.0029) and OS (35.93 months for C vs 11 months for T; P = 0.0267). VEGF AV rs699947 A>C was statistically significant for PFS (17 months for A vs 3.97 months for C; P = 0.0023) and OS (35.93 months for A vs 10.98 for C; P = 0.0272). VEGF AVI rs2010963 G>C was significant in PFS (16.98 months for G vs 4.65 for G/C vs 2.73 for C; P = 0.0188). VEGR3 III rs6877011 C>G was significant in PFS (8.22 months for C vs 2.22 for C/G; P = 0.0361) and OS (35.93 months for C vs 12.08 for C/G; P = 0.0183). Conclusions: In our analysis patients with C polymorphism of rc833061 , A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line. These polymorphisms of the VEGF-A gene are probably connected with a better control of the neoangiogenesis process during TKIs therapy, maybe leading to vasculature normalization. Patients with C polymorphism of rs6877011 seem equally to have a favourable impact in first line therapy. VEGFR-3 role is still matter of debate but seems to be involved in vessels sprouting and architecture.

Abstract 4127: Levels of circulating CD45dimCD34+VEGFR2+ progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with targeted therapies

Abstract Background: A biomarker allowing to predict the efficacy of targeted therapies would be of great clinical value in patients with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell levels are associated with clinical outcome in mRCC patients undergoing targeted treatments. Methods: The TORAVA trial was a randomized phase II study aimed to determine the efficacy and safety of temsirolimus and bevacizumab combination (arm A) in comparison to 2 control arms, sunitinib (arm B) or bevacizumab and α-interferon (arm C). Samples were collected at baseline and day 14 for each treatment arm. CEC levels were analysed in 117 patients (pts) using the CellSearch™ (Veridex, Warren, NJ) platform. Bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell levels were measured in 10ml blood samples of 42 pts by four-color flow cytometry after progenitor cell enrichment. Relation between CEC and CD45dimCD34+VEGFR2+ progenitor cell levels and clinico-biological characteristics, response to treatment (determined by RECIST criteria after 2 cycles) and progression free survival (PFS) was examined. Results: CEC levels were significantly higher in patients without nephrectomy (p<0.001). A trend between the association of high CEC levels and a PS of 2 was observed (p=0.08). CEC and CD45dimCD34+VEGFR2+ progenitor cell levels at both baseline and day 14 were not correlated to response to treatment. No correlation was found between baseline or day 14 CEC values and PFS. However, pre-treatment CD45dimCD34+VEGFR2+ progenitor cell levels were significantly correlated to PFS (p=0.003). Patients with elevated pre-treatment levels of CD45dimCD34+VEGFR2+ progenitor cell had an increased risk of tumor progression. Conclusion: Our results indicate that pre-treatment CD45dimCD34+VEGFR2+ progenitor cell levels could accurately predict PFS in MRCC patients receiving targeted therapies. The association between CEC and CD45dimCD34+VEGFR2+ progenitor cell levels and overall survival will be presented. These data suggested that measurement of CD45dimCD34+VEGFR2+ progenitor cell levels before targeted therapy in mRCC patients will allow to identify at an early stage patients who will benefit most from treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2011-4127

Choi response criteria for prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib

5044 Background: Sunitinib (SU) has been approved for the treatment of metastatic renal cell cancer (mRCC). Since SU can induce extensive necrosis, RECIST may be inappropriate for tumor response evaluation. We evaluated whether the new Choi criteria (J Clin Oncol. 2007;25:1753–1759) are of additional value to predict outcome in mRCC patients (pts) treated with SU. Methods: 56 mRCC pts treated with SU were included. Imaging data consisted of thoracic and abdominal helical CT scans at baseline, after a median of 2 months and were repeated during treatment. For Choi criteria the longest diameter was ≥15 mm. Density of these lesions was determined in Hounsfield units. According to Choi criteria partial response (PR) was defined as ≥10% decrease in size or ≥15% decrease in density, while progressive disease (PD) was defined as ≥10% increase in size without meeting PR criteria by density. Progression-free survival (PFS) and overall survival (OS) were calculated according to Kaplan-Meier. Log rank test was used to test the statistical difference between survival curves. Results: For RECIST and Choi criteria, respectively, 230 and 156 tumor lesions were eligible. At first evaluation, according to RECIST 7 pts had PR, 39 stable disease (SD), and 10 PD, while according to Choi criteria 33 pts had PR, 8 SD and 15 PD. The median tumor density decreased significantly (Wilcoxon Signed Ranks test, p ≤ 0.001). At first evaluation in patients with PR, Choi criteria had a significantly better predictive value for PFS and OS (p < 0.001 and p < 0.001, respectively) than RECIST (p = 0.384 and p = 0.392, respectively). When best response during treatment was analyzed according to RECIST, the predictive value of RECIST increased for both PFS and OS (p = 0.004 and p = 0.002, respectively). For clinical benefit (PR+SD), the predictive value of RECIST and Choi criteria for PFS and OS were comparable (both p < 0.001). Conclusions: Choi criteria can be easily applied on contrast-enhanced CT scans. RECIST and Choi criteria have similar predictive value for outcome in pts with clinical benefit. Choi criteria, however, are more useful to early define a large pt population with favourable clinical outcome. [Table: see text]