Contrast-Enhanced CT Density Predicts Response to Sunitinib Therapy in Metastatic Renal Cell Carcinoma Patients.
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ABSTRACT:
SUBMITTER: Matoori S
PROVIDER: S-EPMC5496476 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients.Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out.The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05).Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
| S-EPMC4037833 | biostudies-other
Project description:PurposeTo develop and validate the radiomics nomogram that combines clinical factors and radiomics features to estimate overall survival (OS) in patients with clear cell renal cell carcinoma (ccRCC), and assess the incremental value of radiomics for OS estimation.Materials and methodsOne hundred ninety-four ccRCC cases were included in the training cohort and 188 ccRCC patients from another hospital as the test cohort. Three-dimensional region-of-interest segmentation was manually segmented on multiphasic contrast-enhanced abdominal CT images. Radiomics score (Rad-score) was calculated from a formula generated via least absolute shrinkage and selection operator (LASSO) Cox regression, after which the association between the Rad-score and OS was explored. The radiomics nomogram (clinical factors + Rad-score) was developed to demonstrate the incremental value of the Rad-score to the clinical nomogram for individualized OS estimation, which was then evaluated in relation to calibration and discrimination.ResultsRad-score, calculated using a linear combination of the 11 screened features multiplied by their respective LASSO Cox coefficients, was significantly associated with OS. Calibration curves showed good agreement between the OS predicted by the nomograms and observed outcomes. The radiomics nomogram presented higher discrimination capability compared to clinical nomogram in the training (C-index: 0.884; 95% CI: 0.808-0.940 vs. 0.803; 95% CI: 0.705-0.899, P < 0.05) and test cohorts (C-index: 0.859; 95% CI: 0.800-0.921 vs. 0.846; 95% CI: 0.777-0.915, P < 0.05).ConclusionsThe radiomics nomogram may be used for predicting OS in patients with ccRCC, and radiomics is useful to assist quantitative and personalized treatment.
| S-EPMC8268016 | biostudies-literature
Project description:Current imaging criteria for categorising disease response in metastatic renal cell carcinoma (mRCC) correlate poorly with overall survival (OS) in patients on anti-angiogenic therapies. We prospectively assess diffusion-weighted and multiphase contrast-enhanced (MCE) MR imaging (MRI) as markers of outcome.Treatment-naive mRCC patients on a phase II trial using sunitinib completed an MRI substudy. Whole-tumour apparent diffusion coefficient (ADC) maps and histograms were generated, and mean ADC and AUC(low) (proportion of the tumour with ADC values lying below the 25th percentile of the ADC histogram) recorded. On MCE-MRI, regions of interest were drawn around the most avidly enhancing components to analyse enhancement parameters. Baseline (n=26) and treatment-related changes in surviving patients (n=20) were correlated with OS. Imaged metastases were also analysed.Forty-seven per cent of the patients showed significant changes in whole-tumour mean ADC following therapy, but there was no correlation with outcome. Patients with a high baseline AUC(low) and greater-than-median AUC(low) increase had reduced OS (HR=3.67 (95% confidence interval (CI)=1.23-10.9), P=0.012 and HR=3.72 (95% CI=0.98-14.21), P=0.038, respectively). There was no correlation between MCE-MRI parameters and OS. Twenty-eight metastases were analysed and showed positive correlation with primary tumour mean ADC for individual patients (r=0.607; P<0.001).Primary RCC ADC histogram analysis shows dynamic changes with sunitinib. Patients in whom the tumour ADC histogram demonstrated high baseline AUC(low) or a greater-than-median increase in AUC(low) with treatment had reduced OS.
| S-EPMC3915138 | biostudies-literature
Project description:Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-?). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy. Sunitinib alone causes significant side effects and has a distinct profile with diarrhoea, hypertension, skin effects hypothyroidism, fatigue and nausea of special interest. The recommended dose of sunitinib in mRCC is 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment (4/2 schedule). An alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems to be of similar efficacy and better tolerability and could be more widely used in the future. An intermittent treatment strategy with a stop in remission and re-induction after progression showed efficacy in smaller trials and is currently being evaluated in a phase III trial. Direct comparison of sunitinib with pazopanib in first-line treatment showed a similar efficacy for both TKIs with a distinct toxicity profile. Data from two phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives. Currently, after immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting. The future will show the position of sunitinib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors.
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Project description:OBJECTIVE:To evaluate the value of 2-dimensional (2D) and 3-dimensional (3D) computed tomography texture analysis (CTTA) models in distinguishing fat-poor angiomyolipoma (fpAML) from chromophobe renal cell carcinoma (chRCC). METHODS:We retrospectively enrolled 32 fpAMLs and 24 chRCCs. Texture features were extracted from 2D and 3D regions of interest in triphasic CT images. The 2D and 3D CTTA models were constructed with the least absolute shrinkage and selection operator algorithm and texture scores were calculated. The diagnostic performance of the 2D and 3D CTTA models was evaluated with respect to calibration, discrimination, and clinical usefulness. RESULTS:Of the 177 and 183 texture features extracted from 2D and 3D regions of interest, respectively, 5 2D features and 8 3D features were selected to build 2D and 3D CTTA models. The 2D CTTA model (area under the curve [AUC], 0.811; 95% confidence interval [CI], 0.695-0.927) and the 3D CTTA model (AUC, 0.915; 95% CI, 0.838-0.993) showed good discrimination and calibration (P > .05). There was no significant difference in AUC between the 2 models (P = .093). Decision curve analysis showed the 3D model outperformed the 2D model in terms of clinical usefulness. CONCLUSIONS:The CTTA models based on contrast-enhanced CT images had a high value in differentiating fpAML from chRCC.
| S-EPMC6801892 | biostudies-other
Project description:The aim of this study was to compare fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and contrast-enhanced computed tomography (CE-CT) for the prediction of progression-free survival (PFS) and disease-specific survival (DSS) in patients with stage IV breast cancer undergoing systemic therapy.Sixty-five patients with metastatic breast cancer treated with first- or second-line systemic therapy in prospective clinical trials were included. Response to treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for CE-CT and by PET Response Criteria in Solid Tumors (PERCIST), respectively.All responders by RECIST (n = 22) were also responders by PERCIST, but 40% (17/43) of non-responders by RECIST were responders by PERCIST. Responses according to RECIST and PERCIST both correlated with PFS, but PERCIST showed a significantly higher predictive accuracy (concordance index for PFS: 0.70 vs. 0.60). One-year PFS for responders vs. non-responders by RECIST was 59% vs. 27%, compared to 63% vs. 0% by PERCIST. Four-year DSS of responders and non-responders by RECIST was 50% and 38%, respectively (p = 0.2, concordance index: 0.55) as compared to 58% vs. 18% for PERCIST (p < 0.001, concordance index: 0.65). Response on PET/CT was also a significantly better predictor for DSS than disease control on CE-CT.In patients with metastatic breast cancer, tumor response on PET/CT appears to be a superior predictor of PFS and DSS than response on CE-CT. Monitoring tumor response by PET/CT may increase the power of clinical trials using tumor response as an endpoint, and may improve patient management in clinical routine.
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Project description:VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression. Receptor tyrosine kinase (RTK) inhibitors such as sunitinib have been demonstrated to target tumorigenic signaling pathways, delay tumor progression, and improve patient prognosis in metastatic renal cell carcinoma (mRCC). Although several mechanisms of sunitinib resistance have been reported, the solutions to overcome this resistance remain unclear. In our study, we found that increased expression of Y-box binding protein 1 (YB1, a multidrug resistance associated protein) and EphA2 (a member of the erythropoietin-producing hepatocellular (Eph) receptor family, belonging to the RTK family) mediated sunitinib resistance and mRCC exhibited a large phenotypic dependence on YB1 and EphA2. In addition, our findings confirm that YB1 promotes the invasion, metastasis and sunitinib resistance of ccRCC by regulating the EphA2 signaling pathway. Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells, suppressed tumor growth in vivo, and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stability of EphA2 through inhibition of the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted.
| S-EPMC7498371 | biostudies-literature
Project description:Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ?6 yr.To analyze long-term safety with sunitinib in mRCC patients.Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g., cytokine refractory or treatment-naïve).Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (?2 yr) sunitinib treatment.Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ?3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients.Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative.More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk.
| S-EPMC5032140 | biostudies-literature
Project description:There are currently several options for tyrosine kinase inhibitor as a systemic therapy for metastatic renal cell carcinoma (mRCC). The successful control of adverse events caused by such drugs, along with eliciting long-term maximum effect, are the major issues with respect to the treatment strategy for mRCC. We herein report the clinical course of mRCC, in which erythema multiforme major was observed on the 13th day of the first course of sunitinib, but the symptoms improved after the immediate withdrawal of sunitinib, as well as the administration of topical steroids and oral antihistamines alone.
| S-EPMC6558298 | biostudies-literature
Project description:Following approval of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate for the treatment of patients with metastatic renal cell carcinoma (mRCC) in Europe and the USA in 2006, the agent has had a substantial impact on the treatment landscape in this setting. Sunitinib is now recommended in international treatment guidelines for the first-line treatment of favourable- or intermediate-risk mRCC and as an alternative option in poor-risk mRCC. In the 6 years since the approval of sunitinib, the range of agents available for the treatment of mRCC has expanded substantially, and this, together with a number of additional therapies in late-stage development, has increased the treatment options available to patients. Results from a phase III trial and a global expanded access study have provided robust data to support the efficacy of sunitinib in mRCC, including in real-world populations. Data also suggest a significant quality of life benefit with sunitinib, with superior patient-reported outcomes observed with this agent compared with interferon-α therapy. Both clinical and real-world study data also support the safety profile of sunitinib; most treatment-associated adverse events are mild to moderate in severity and can be managed effectively with close monitoring and proactive management. Clinical experience with sunitinib has demonstrated that therapy management, involving optimal dosing, maximum treatment duration and prompt and effective adverse event management, supports optimal patient outcomes with sunitinib. In this review we discuss clinical experience with sunitinib in mRCC, with an emphasis on real-world data, and utilize clinical case studies to examine the successful implementation of therapy management strategies for optimal patient outcomes. An increasing body of evidence suggests that side effects associated with sunitinib therapy, including hypertension, hand-foot syndrome and hypothyroidism, may represent effective markers of treatment response, and these will also be discussed.
| S-EPMC3441135 | biostudies-literature