PROJECT SUMMARY/ABSTRACT Delivering dose to cancers while sparing normal tissue is the ultimate goal in radiotherapy treatment, especially in the head and neck. By identifying tumors which are more likely to respond early in treatment, as well as subvolumes of resistant tumor, radiotherapy plans could be changed each day to take advantages of biological alteration in the tumor, resulting in reduced side effects with equivalent probability of cure. Functional imaging techniques, such as diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM), have demonstrated utility in clinical series in discriminating early responders to radiation therapy in head and neck cancers, as well as identifying radiation resistant disease post-therapy. These functional imaging techniques could be utilized to actively adapt radiation therapy with high frequency during the radiation treatment course, without requiring exogenous contrast or tracer administration. The University of Texas M.D. Anderson Cancer Center, Elekta Medical Systems and Philips Healthcare are jointly developing a combination imaging/therapy delivery device, which combines a 1.5 Tesla MRI with a linear accelerator. The MR-LinAc device provides the capacity to acquire functional and anatomic imaging data daily, in the treatment position, while simultaneously delivering radiotherapy. The proposed project is a five-year technology development strategy that will ultimately result in a unified workflow for quantitative functional imaging guided semi-automated dose modification during head and neck radiotherapy. This project will implement state of the art simultaneous anatomic and DWI image acquisition, spatially accurate dose and image registration, physical and digital phantom-based quality assurance, software tracking of cumulative region of interest dose, serial tracking of apparent diffusion coefficient (ADC) maps, and anatomic and functional imaging constraint based serial re-optimization. Finally, we will leverage data from prospective head and neck cancer MRI clinical trials to validate and harden the proposed imaging acquisition/quality assurance/software workflow in order to demonstrate clinical feasibility and estimate potential for toxicity reduction and clinical utility. Successful completion of this project will result in a method for monitoring functional imaging changes to tumor and normal tissue daily during radiotherapy. This method can be used to generate data to assess the dose to the organs and critical structures and can be used to maximize the dose to the tumor and/or minimize the risk of complications to normal tissue. The resulting data can also be used to study dose-related treatment side effects. The ultimate goal of utilizing this technology is to improve the delivery of radiotherapy treatments and the quality of life of radiotherapy patients.