Refinement of soft tissue targeting and alignment protocols is small animal radiotherapy using an injectable fiducial marker

Animal models are central for the development of medical therapies including radiotherapy. Animal experiments often fail to accurately replicate the clinical scenario resulting in only approximately one third of highly cited animal research studies translating at the level randomised human trials. The recent development of small animal image guided radiotherapy devices (IGRT) has allowed radiotherapy studies in small animal to more accurately replicate complex dose distributions and fractionated protocols used in the clinic which will ultimately increase the translational impact of animal studies in driving radiotherapy trials.

Small animal IGRT uses on-board cone beam computed tomography (CBCT) imaging to deliver small radiation fields with high precision and accuracy, and reduces the volume of normal tissue irradiated within the target field. Whilst this is a significant refinement over conventional radiation exposure procedures performed without image guidance and often targeting large volumes of normal tissue, there remains a number of limitations associated with accurate soft tissue targeting, set-up error and target position uncertainty.

Our aim is to reverse translate a clinically validated solution using injectable, radio-opaque liquid fiducial markers that can be positioned in, or in close proximity to the target volume. This approach remains challenging in animal models given the small target volumes, however, using a minimally invasive injectable marker provides an optimal solution to improve target alignment. This will involve the injection of a small volume of a low viscosity, biocompatible iodinated carbohydrate material to provide excellent visibility with minimal CT image and dose artefact.

Within the framework of the NC3Rs we will initially replace in vivo characterisation of our marker with in phantom measurements of CBCT and MRI image contrast enhancement. We will perform detailed mathematical simulations to predict the impact on radiobiological responses in tumour and normal tissues. Using appropriately powered experiments in mouse models, we will characterise the fiducial marker in multiple tumour and normal tissue sites and determine impacts on radiobiological response. This approach is a major refinement of existing procedures allowing visualisation soft tissue that will significantly reduce target position uncertainty and improve dosimetry leading to the improved reproducibility and reduced animal numbers in preclinical radiotherapy studies. Through our collaborators at the National Physical Laboratory, the Clinical and Translational Radiotherapy Research Working Group of the National Cancer Institute and Xstrahl Life Sciences, our findings will be disseminated to the UK national radiotherapy research community to maximise the potential of widespread uptake of novel alignment and targeting protocols in preclinical radiotherapy studies.