| In biologically-conformal radiation therapy, or dose painting, functional imaging is used to define biological targets for radiotherapy dose escalation. There is still much uncertainty about which imaging target is optimal for dose painting, and how dose should be prescribed inside the target volume. The goal of this dissertation was to investigate and characterize the properties of different biological imaging methods that make them good or poor candidates to serve as dose painting targets, and to evaluate how dose is likely to be prescribed to target volumes. Using spontaneous sinonasal tumors in canines treated with radiation therapy as research models, we related FDG, FLT, and Cu-ATSM PET uptake---surrogate measures of metabolism, proliferation, and hypoxia, respectively---to radiation resistance using outcome analysis and voxel-wise spatial analysis. We also investigated the similarities and spatio-temporal stability of the different tracer uptake patterns. Overall, we found that FLT-based biomarkers, especially those acquired during the course of radiation therapy, were the best biomarkers at predicting outcome following radiation therapy. Using spatial analysis, we found that all tracers had comparable performances in identifying resistant tumor subvolumes, and that there was large interpatient heterogeneity in how well PET tracer distributions could identify resistant subvolumes. We also demonstrated that spatial distributions of Cu-ATSM and FLT uptake measured during therapy were very similar to those measured at baseline, indicating FLT and Cu-ATSM PET as spatially-robust targets for dose painting. Finally, we demonstrate how FDG, FLT, and Cu-ATSM dose painting prescriptions are likely to be applied in human head-and-neck tumors, and confirm the feasibility of accurately delivering dose painting plans with tomotherapy. Overall, we did not find a single imaging method that stood out as the most promising target for dose painting. Rather, all tracers demonstrated evidence both for and against their use as dose painting targets. However, through these studies, we now have a greater understanding of the characteristics and limitations of dose painting according to different biological targets, which can help guide the development of future dose painting studies. |
