Abstract
ObjectivesTo investigate a multimodal, multiparametric perfusion MRI / 18F-fluoro-deoxyglucose-(18F-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation.Materials and MethodsHuman colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group; n = 7 control group) female athymic nude rats (Hsd:RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/18F-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV, %) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In 18F-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67).ResultsRegorafenib significantly (p<0.01) suppressed PF (81.1±7.5 to 50.6±16.0 mL/100mL/min), PV (12.1±3.6 to 7.5±1.6%) and PS (13.6±3.2 to 7.9±2.3 mL/100mL/min) as well as TTB (3.4±0.6 to 1.9±1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0±2.4 vs. 16.1±5.9) and tumor cell proliferation (Ki-67, 434.0 ± 62.9 vs. 663.0 ± 98.3) in the therapy group. Perfusion MRI parameters ΔPF, ΔPV and ΔPS showed strong and significant (r = 0.67-0.78; p<0.01) correlations to the PET parameter ΔTTB and significant correlations (r = 0.57-0.67; p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55; p<0.05).ConclusionsA multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and 18F-FDG-PET validated by immunohistochemistry.
Highlights
In recent years a broad range of novel molecular cancer therapeutics were introduced into clinical use [1,2,3]
A multimodal, multiparametric perfusion magnetic resonance imaging (MRI)/positron emission tomography (PET) imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and 18F-FDG-PET validated by immunohistochemistry
A multiparametric characterization of treatment effects with the assessment of different aspects of tumor metabolism under therapy, e.g. glucose metabolism quantified by 18F-FDG PET, is of particular interest to acquire a multi-facetted chart of treatment effects and to reveal potential interdependencies between the different acquired parameters of tumor pathophysiology
Summary
In recent years a broad range of novel molecular cancer therapeutics were introduced into clinical use [1,2,3]. Regorafenib, an oral multi tyrosine kinase inhibitor, showed in vivo antiangiogenic and anti-proliferative effects in different experimental tumor models, such as breast cancer, renal cell carcinoma and glioblastoma and has proven effectiveness in the clinical treatment of metastatic colorectal cancer [7,8]. These new therapy regimes demonstrated significant effects on tumor angiogenesis and tumor metabolism, but often only subtle effects on tumor morphology, in early stages of tumor treatment [9]. Multimodality hybrid imaging protocols such as MRI/PET are able to assess a number of functional imaging parameters in a one-stop-shop approach, including tumor perfusion and glucose metabolism, allowing for an intraindividual comparison and validation of the parameters
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