Temporal evolution of apparent diffusion coefficient MRI and [18F]-FLT PET imaging biomarkers in response to gefitinib therapy

Objectives To describe the temporal behaviour of Apparent Diffusion Coefficient (ADC) and [18F]-3'-deoxy-3'-fluorothymidine ([18F]-FLT) imaging biomarkers, and their relationship to biological changes with and without gefitinib therapy, in PC9 xenografts in mice. This study contributes to the QuIC ConCePT consortium project which seeks to qualify ADC MRI and [18F]-FLT PET as efficacy biomarkers for oncology.

Methods Vehicle and gefitinib treated mice (clinically relevant dose of 6.25 mg/kg/d, p.o.) bearing EGFR-TKI sensitive PC9 subcutaneous xenografts were imaged at baseline (BL) & 24h, BL & 48h or BL & 96h of treatment. Tumour meanADC values were calculated from diffusion-weighted MRI. Dynamic [18F]-FLT PET data was acquired over 60 minutes. Static and kinetic data were derived. Imaging data was cross validated with histopathology markers of cell death and proliferation.

Results Gefitinib caused a significant effect on tumour volume from 48hrs onwards (p < 0.05). A significant effect on meanADC was observed at 24hrs (p=0.019), prior to changes in tumour volume and again at 96 hrs (p=0.009). There were no significant changes in static PET imaging parameters such as MaxSUV and MeanSUV with gefitinib therapy. Compartmental analysis revealed significant changes in the K1/k2 ratio (p < 0.011) which reflects radiotracer delivery and the k3/k4 ratio (p < 0.001) which reflects radiotracer metabolism. KFlux was significantly changed at 24 hours (p < 0.01). Significant effects on kinetic parameters were also seen at other timepoints, with the greatest effect on k3/k4 at 96 hours post treatment.

Conclusions Changes in ADC MRI were observed after only 24hrs of 6.25 mg/kg gefitinib. [18F]-FLT was not able to detect treatment effects using SUV approaches. Biological interpretation of the imaging data will be reported via cross correlation of imaging data with histopathology.