Assessment of Response to Tyrosine Kinase Inhibitors in Metastatic Renal Cell Cancer: CT Texture as a Predictive Biomarker
TL;DR: CT texture analysis reflecting tumor heterogeneity is an independent factor associated with time to progression and has potential as a predictive imaging biomarker of response of metastatic renal cancer to targeted therapy.
Abstract: Purpose: To assess the changes in tumor CT texture following 2 cycles of TKIs; and to determine if tumor texture correlates with measured time to progression in metastatic renal cell cancer treated with TKIs
Materials and Methods: Institutional review board waiver was obtained for this retrospective analysis Contrast enhanced CT texture parameters were assessed in 39 patients with metastatic renal cell cancer treated with a TKI 87 metastases were analysed at baseline and following 2 cycles of treatment: changes in tumor entropy and uniformity, derived using a software algorithm that selectively filters and extracts texture at different scales (fine to coarse detail: 10 to 25), were recorded Response assessment was also obtained using RECIST, Choi and modified Choi criteria The correlation of texture parameters and standard criteria to measured time to progression was assessed by Kaplan-Meier analysis and a Cox regression model Statistical significance was set at 5%
Results: Tumor entropy decreased by 3-45% and uniformity increased by 5-21% for the different scale values following TKI treatment Using a threshold change of ≤-2% for uniformity at a coarse scale value of 25, Kaplan Meier curves of the proportion of patients without disease progression were significantly different, and better than for standard response assessment (p=0008 versus p=0267, p=0053, p=0042 for RECIST, Choi, and Modified Choi criteria respectively) Cox regression analysis showed that texture uniformity was an independent predictor of time to progression (odds ratio, OR =402; 95% CI 152,1065; p=0005)
Conclusion: CT texture analysis, reflecting tumor heterogeneity, is an independent factor associated with time to progression, and has potential as a predictive imaging biomarker of response of metastatic renal cancer to targeted therapy
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TL;DR: An overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date is provided and the technical challenges that have limited its widespread clinical implementation so far are described.
Abstract: Tumor spatial heterogeneity is an important prognostic factor, which may be reflected in medical images Image texture analysis is an approach of quantifying heterogeneity that may not be appreciated by the naked eye. Different methods can be applied including statistical-, model-, and transform-based methods. Early evidence suggests that texture analysis has the potential to augment diagnosis and characterization as well as improve tumor staging and therapy response assessment in oncological practice. This review provides an overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date and describes the technical challenges that have limited its widespread clinical implementation so far. With further efforts to refine its application, image texture analysis has the potential to develop into a valuable clinical tool for oncologic imaging. • Tumor spatial heterogeneity is an important prognostic factor. • Image texture analysis is an approach of quantifying heterogeneity. • Different methods can be applied, including statistical-, model-, and transform-based methods. • Texture analysis could improve the diagnosis, tumor staging, and therapy response assessment.
730 citations
Cites background from "Assessment of Response to Tyrosine ..."
...…carcinoma Texture analysis Percentage change in coarse texture uniformity of≤−2 % after 2 cycles of TKI correlated with shorter time to progression Goh et al., 2011 [41] Prognosis assessment Liver texture in patients with colorectal cancer but no known metastases Texture analysis Coarse…...
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TL;DR: Although CTTA CT texture analysis seems to be a promising imaging biomarker, there is marked variability in methods, parameters reported, and strength of associations with biologic correlates.
Abstract: CT texture analysis of tumor heterogeneity has shown promise in lesion characterization, pretreatment tumor assessment, and response evaluation for some tumor types and may also have a spectrum of potential nononcologic applications, including assessment of hepatic and pulmonary fibrosis; however, a variety of challenges, including standardization of segmentation/measurement, postprocessing, and reporting, as well as ongoing delineation of pathologic correlates, need to be resolved before widespread implementation.
540 citations
TL;DR: This article discusses how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function and considers how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation.
Abstract: Tumors exhibit genomic and phenotypic heterogeneity which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks. These methods can establish whether one tumor is more or less heterogeneous than another and can identify sub-regions with differing biology. In this article we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, rather than be developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care.
471 citations
TL;DR: This Review addresses the critical issues to ensure the proper development of radiomics as a biomarker and facilitate its implementation in clinical practice.
460 citations
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...2011 [96] T: 39 First-order statistics (Entropy...
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TL;DR: This review focuses on the literature describing the emerging methods of texture analysis in 18FDG PET/CT, as well as other imaging modalities, and how the measurement of spatial variation of voxel grey-scale intensity within an image may provide additional predictive and prognostic information, and postulate the underlying biological mechanisms.
Abstract: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is now routinely used in oncological imaging for diagnosis and staging and increasingly to determine early response to treatment, often employing semiquantitative measures of lesion activity such as the standardized uptake value (SUV). However, the ability to predict the behaviour of a tumour in terms of future therapy response or prognosis using SUVs from a baseline scan prior to treatment is limited. It is recognized that medical images contain more useful information than may be perceived with the naked eye, leading to the field of “radiomics” whereby additional features can be extracted by computational postprocessing techniques. In recent years, evidence has slowly accumulated showing that parameters obtained by texture analysis of radiological images, reflecting the underlying spatial variation and heterogeneity of voxel intensities within a tumour, may yield additional predictive and prognostic information. It is hoped that measurement of these textural features may allow better tissue characterization as well as better stratification of treatment in clinical trials, or individualization of future cancer treatment in the clinic, than is possible with current imaging biomarkers. In this review we focus on the literature describing the emerging methods of texture analysis in 18FDG PET/CT, as well as other imaging modalities, and how the measurement of spatial variation of voxel grey-scale intensity within an image may provide additional predictive and prognostic information, and postulate the underlying biological mechanisms.
421 citations
Cites background from "Assessment of Response to Tyrosine ..."
...studied patients with renal carcinoma treated with tyrosine kinase inhibitors and found that changes in textural features related to heterogeneity of CT images are independent predictors of time to progression [46]....
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References
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TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.
20,760 citations
TL;DR: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa.
Abstract: Background Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted. Methods We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety. Results The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001). Conclusions Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889).
5,244 citations
TL;DR: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects.
Abstract: Background We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma. Methods From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. Results At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44;...
4,592 citations
TL;DR: Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
Abstract: Purpose Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). Patients and Methods Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. Conclusion Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC. J Clin Oncol 28:1061-1068. © 2010 by American Society of Clinical Oncology
2,260 citations
TL;DR: The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC, as second-line therapy in a setting where no effective systemic therapy is presently recognized.
Abstract: Purpose Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC. Patients and Methods Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting ≥ 3 months. Median time to progression in the 6...
1,609 citations