Dynamic functional imaging of the response of lung tumours to a potential hypoxia modifier

Thesis

In this thesis, the kinetics of fluoromisonidazole (FMISO) uptake by lung tumours in patients with advanced stage non-small cell lung cancer (NSCLC) is analysed. The uptake data was extracted from dynamic positron emission tomography (PET) images collected in the course of a clinical trial designed to investigate the impact of Buparlisib, a potentially hypoxia-modifying drug, on perfusion and hypoxia in NSCLC patients. The trial design is a 3+3 dose escalation study exploring the effect of daily doses of 50 mg (Cohort 1), 80 mg (Cohort 2), and 100 mg (Cohort 3) Buparlisib.

Many trials combining drug and RT fail in the clinical setting despite yielding promising pre-clinical data: the work described here uses and develops kinetics analysis techniques that can be applied to proof-of-principle dynamic PET imaging studies. For whole tumour FMISO kinetics analysis it has been shown that an irreversible three-compartment model is optimal, whereas for voxel-by-voxel analysis an irreversible two-compartment model is optimal. A clustering method is also presented to distil the information from the noisy voxel-by-voxel kinetics data into the minimum number of clusters that adequately describe the data.

Analysis of both PET kinetics and perfusion CT has shown significant decreases in the rate of tracer flow from blood into the tumour post-Buparlisib (in Cohorts 2 and 3). Voxel-by-voxel analysis found that this occurred throughout the tumour volume. The volume of blood within the tumour was shown to increase significantly after Buparlisib according to the PET kinetics analysis, whereas analysis of perfusion CT data showed a decrease post-Buparlisib. For Cohorts 2 and 3, significant decreases were seen in tumour volumes hypothesised to be hypoxic (tumour-to-blood ratio greater than 1.4) after administration of Buparlisib. The estimated FMISO intracellular binding rate-constant (associated with cellular oxygen concentration) according to the voxel-by-voxel kinetics analysis was found to significantly decrease at the tumour edge and significantly increase in the tumour centre, with an overall decrease for Cohort 3.

Authors: McGowan, D

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English