The effectiveness of radiation therapy for lung cancer treatment can be significantly improved if radiation dose can be safely escalated. The main limitation to dose escalation is tumor location uncertainty during treatment due to patient respiration. In addition to geometric changes, tumor hypoxia is a leading cause of treatment failure. If dose can be escalated to radioresistant hypoxic regions then local tumor control would also improve. RefleXion Medical is using positron emission tomography (PET) to guide radiation delivery so that both geometric and biological changes in the tumor can be accounted for in real-time during treatment. In Phase I of the project we aim to: 1) Develop a method of directing radiation beam-lets along individual PET lines-of- response;2) Develop a method of estimating target position using subsets of PET emissions that occur over a short period of time;and 3) Test methods developed in Aims 1 and 2 using list-mode PET data acquired from a moving phantom. Aim 3 experiments will be accomplished at the Stanford Cancer Center utilizing a motion phantom and a PET-CT system. In Phase II we plan to directly control a multi-leaf collimator using a motion phantom and PET detector table-top system so that tumor tracking can be demonstrated experimentally. The developed treatment methods for real-time PET-guided radiation therapy may result in significantly more effective treatments through safe dose escalation and optimal distribution of the dose to the heterogeneous moving tumor. PUBLIC HEALTH RELEVANCE: Lung cancer is the biggest cancer killer in both men and women in the U.S. While two-thirds of U.S cancer patients are treated with radiation therapy, success rates for lung cancer are low, largely due to movement of the tumor during breathing. In this project, RefleXion Medical aims to develop a radiotherapy system that uses positron emission tomography (PET) to non-invasively track a tumor's position and biological state during treatment. Real-time PET-guided radiotherapy will enable safe dose escalation and smarter dose distribution, leading to more effective treatment of tumors that exhibit significant motion.