Correlation of Perfusion MRI and 18F-FDG PET Imaging Biomarkers for Monitoring Regorafenib Therapy in Experimental Colon Carcinomas with Immunohistochemical Validation

Eschbach, Ralf; Fendler, Wolfgang P.; Kazmierczak, Philipp M.; Hacker, Marcus; Rominger, Axel; Carlsen, Janette; Hirner-Eppeneder, Heidrun; Schuster, Jéssica; Moser, Matthias; Havla, Lukas; Schneider, Moritz; Ingrisch, Michael; Spaeth, Lukas; Reiser, Maximilian; Nikolaou, Konstantin; Cyran, Clemens C.

doi:10.1371/journal.pone.0115543

Cited by 6 publications

(8 citation statements)

References 46 publications

(37 reference statements)

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“…DCE-US is highly operator- and patient-dependent and lacks reproducibility due to high inter- and intra-observer variations (18); it has, to our knowledge, not yet been explored in the treatment evaluation of regorafenib. FDG PET-CT as well as DCE-MRI has both shown potential as non-invasive imaging markers of response (19,20).…”

Section: Discussionmentioning

confidence: 99%

Texture in the monitoring of regorafenib therapy in patients with colorectal liver metastases

et al. 2019

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Background The morphological changes seen during treatment with regorafenib represent challenges when evaluating treatment response using RECIST. Computed tomography texture analysis (CTTA) has potential as a non-invasive functional imaging biomarker during treatment with anti-angiogenetic therapies. Purpose To explore changes in three-dimensional tumor CTTA in colorectal liver metastases (CRLM) in a cohort of patients with metastatic colorectal cancer during treatment with regorafenib. Material and Methods Twenty-seven patients with CRLM were treated with regorafenib and evaluated using CTTA. Texture analysis was applied in the standard contrast-enhanced CT performed in the portal-venous phase (PVP-CT) and in two selected scan series derived from a dynamic contrast-enhanced CT (DCE-CT). A total of 269 scan series were analyzed. Results In the unfiltered dataset of the PVP-CT, all texture parameters, except for kurtosis, changed significantly during treatment. In the filtered PVP-CT dataset, the CTTA parameters entropy, uniformity, and standard deviation were markedly associated with overall survival (OS) at spatial scaling factors (SSF) of 1.0– 2.0, but did not change significantly during treatment. Skewness increased significantly during treatment and was evaluated at SSF ≥1.0. In general, the same trends in texture parameter changes were seen when analyzing DCE-CT datasets. However, these changes did not reach the same level of significance. Conclusions In this exploratory study, we demonstrated substantial changes in the texture parameters during treatment with regorafenib, most evident in the unfiltered dataset of the PVP-CT. Some texture parameters showed prognostic association with OS. Texture may potentially help evaluate the treatment response in patients treated with regorafenib.

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Section: Discussionmentioning

confidence: 99%

Texture in the monitoring of regorafenib therapy in patients with colorectal liver metastases

et al. 2019

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“…Angiogenesis has been demonstrated to play a pivotal role in CRC and overexpression of VEGF and high vascular density in primary CRCs are associated with an increased risk of tumor recurrence and the formation of metastases [1]. Regorafenib is an oral multi tyrosine kinase inhibitor that showed anti-angiogenic and anti-proliferative effects in vivo in several experimental tumor models, like breast cancer, renal cell carcinoma and glioblastoma [3]. Regorafenib has demonstrated a significant improvement in overall survival in a phase III study in patients with metastatic CRC who failed previous therapies [1].…”

Section: Introductionmentioning

confidence: 99%

“…While anti-angiogenic, not primarily cytotoxic tumor therapeutics such as regorafenib have been shown to exhibit significant effects on tumor angiogenesis and metabolism, only subtle effects were observed on tumor size and morphology, particularly in the first phase following therapy initiation [3,6]. In this context, approved methods of monitoring primarily cytotoxic cancer therapies, such as the morphology-based Response Evaluation Criteria in Solid Tumors (RECIST), are not adequately sensitive for a reliable monitoring of the early therapeutic effects of molecular anti-angiogenic therapeutics [3,6–8].…”

Section: Introductionmentioning

confidence: 99%

“…In this context, approved methods of monitoring primarily cytotoxic cancer therapies, such as the morphology-based Response Evaluation Criteria in Solid Tumors (RECIST), are not adequately sensitive for a reliable monitoring of the early therapeutic effects of molecular anti-angiogenic therapeutics [3,6–8]. Alternatively, functional and molecular imaging biomarkers assessed by multiparametric imaging methods such as contrast-enhanced ultrasound (CEUS) may provide a sensitive tool for an early and reliable therapy monitoring of molecular, anti-angiogenic drugs.…”

Section: Introductionmentioning

confidence: 99%

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Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

et al. 2017

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ObjectivesTo investigate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for monitoring therapy effects of regorafenib on experimental colon carcinomas in rats with correlation to dynamic contrast-enhanced MRI (DCE-MRI) and immunohistochemistry.Materials and MethodsHuman colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 21 (n = 11 therapy group; n = 10 control group) female athymic nude rats (Hsd: RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment with regorafenib or a placebo (10 mg/kg bodyweight), using CEUS with VEGFR2-targeted microbubbles and DCE-MRI. In CEUS tumor perfusion was assessed during an early vascular phase (wash-in area under the curve = WiAUC) and VEGFR2-specific binding during a late molecular phase (signal intensity after 8 (SI8min) and 10 minutes (SI10min)), using a conventional 15L8 linear transducer (transmit frequency 7 MHz, dynamic range 80 dB, depth 25 mm). In DCE-MRI functional parameters plasma flow (PF) and plasma volume (PV) were quantified. For validation purposes, CEUS parameters were correlated with DCE-MRI parameters and immunohistochemical VEGFR2, CD31, Ki-67 and TUNEL stainings.ResultsCEUS perfusion parameter WiAUC decreased significantly (116,989 ± 77,048 a.u. to 30,076 ± 27,095a.u.; p = 0.005) under therapy with no significant changes (133,932 ± 65,960 a.u. to 84,316 ± 74,144 a.u.; p = 0.093) in the control group. In the therapy group, the amount of bound microbubbles in the late phase was significantly lower in the therapy than in the control group on day 7 (SI8min: 283 ± 191 vs. 802 ± 460 a.u.; p = 0.006); SI10min: 226 ± 149 vs. 645 ± 461 a.u.; p = 0.009). PF and PV decreased significantly (PF: 147 ± 58 mL/100 mL/min to 71 ± 15 mL/100 mL/min; p = 0.003; PV: 13 ± 3% to 9 ± 4%; p = 0.040) in the therapy group. Immunohistochemistry revealed significantly fewer VEGFR2 (7.2 ± 1.8 vs. 17.8 ± 4.6; p < 0.001), CD31 (8.1 ± 3.0 vs. 20.8 ± 5.7; p < 0.001) and Ki-67 (318.7 ± 94.0 vs. 468.0 ± 133.8; p = 0.004) and significantly more TUNEL (672.7 ± 194.0 vs. 357.6 ± 192.0; p = 0.003) positive cells in the therapy group. CEUS parameters showed significant (p < 0.05) correlations to DCE-MRI parameters and immunohistochemistry.ConclusionsCEUS with VEGFR2-targeted microbubbles allowed for monitoring regorafenib functional and molecular therapy effects on experimental colorectal adenocarcinomas with a significant decline of CEUS and DCE-MRI perfusion parameters as well as a significant reduction of specifically bound microbubbles under therapy, consistent with a reduced expression of VEGFR2.

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“…Other imaging techniques also propose new methods for assessing the treatment response as opposed to the standard morphological size-based evaluation. In the treatment evaluation of regorafenib this includes dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and F-18-fluordeoxyglucose positron emission tomography (FDG-PET), both of which have shown potential as non-invasive imaging biomarkers of response (28)(29)(30).…”

Section: D0-2 ¼ Change Between Baseline and 2 Follow-up Evaluationmentioning

confidence: 99%

Dynamic contrast-enhanced computed tomography as a potential biomarker in patients with metastatic colorectal cancer treated with regorafenib

et al. 2018

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Background RECIST 1.1 presents challenges when evaluating treatment response to angiogenesis inhibitors. The objective response rate, when evaluating the treatment effect of regorafenib, using RECIST 1.1, is < 2% and beneficial treatment could erroneously be terminated. Dynamic contrast-enhanced computed tomography (DCE-CT) has potential as a non-invasive functional imaging biomarker, by quantifying the treatment effect of this targeted therapy. Purpose To evaluate three-dimensional (3D) tumor dynamic parameters representing tumor microcirculation assessed by DCE-CT during the treatment with regorafenib in a cohort of patients with treatment-refractory metastatic colorectal cancer. Material and Methods Thirty-three patients with colorectal metastases (27 liver lesions, three abdominal lesions, and three pulmonary lesions) were treated with regorafenib and evaluated using DCE-CT. A total of 112 DCE-CT scans were analyzed using Advanced Perfusion and Permeability Application and correlated to standard contrast-enhanced computed tomography (CE-CT) evaluated using RECIST 1.1. Results A significant decrease in most DCE-CT parameters, a simultaneous decrease in tumor attenuation and an increase in tumor volume were detected during treatment. However, no associations were found between the DCE-CT parameters and PFS or OS using simple COX proportional hazards regression. Conclusion In this exploratory study, a significant decrease in most dynamic parameters suggests an overall treatment effect of regorafenib in tumor vasculature. DCE-CT may assist in an objective evaluation of these responses compared to RECIST. The anti-angiogenic changes could not be associated with treatment outcome in terms of PFS and OS, which might be due to the small cohort or a rather limited survival benefit in this pre-medicated treatment-refractory group of patients.

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Correlation of Perfusion MRI and 18F-FDG PET Imaging Biomarkers for Monitoring Regorafenib Therapy in Experimental Colon Carcinomas with Immunohistochemical Validation

Cited by 6 publications

References 46 publications

Texture in the monitoring of regorafenib therapy in patients with colorectal liver metastases

Texture in the monitoring of regorafenib therapy in patients with colorectal liver metastases

Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

Dynamic contrast-enhanced computed tomography as a potential biomarker in patients with metastatic colorectal cancer treated with regorafenib

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