Correlation of perfusion MRI and 18F-FDG PET imaging biomarkers for monitoring regorafenib therapy in experimental colon carcinomas with immunohistochemical validation

PLoS One. 2015 Feb 10;10(2):e0115543. doi: 10.1371/journal.pone.0115543. eCollection 2015.

Abstract

Objectives: To 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 methods: Human 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).

Results: Regorafenib 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).

Conclusions: A 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / metabolism*
  • Colonic Neoplasms / drug therapy*
  • Drug Monitoring / methods*
  • Female
  • Fluorodeoxyglucose F18
  • Heterografts / pathology
  • Humans
  • Immunohistochemistry / methods
  • Magnetic Resonance Angiography / methods*
  • Neoplasms, Experimental / drug therapy
  • Phenylurea Compounds / therapeutic use*
  • Positron-Emission Tomography / methods*
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Nude

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Phenylurea Compounds
  • Pyridines
  • Fluorodeoxyglucose F18
  • regorafenib

Grants and funding

This study was supported by a research grant (research material only) of Bayer Healthcare (www.bayer.com) and by the German Federal Ministry of Education and Research (BMBF) Excellence Cluster M4 (www.m4.de Grant No. 01EX1021X). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.