The goal of this project is to perform non-randomized clinical studies, seeking to improve the therapeutic ratio of protons by exploiting the potential clinical advantage(s) of the reduced dose bath using optimized intensity modulated protons (IMPT), in clinical sites that we hypothesize will result in reduced non-target radiation dose and normal tissue toxicity. We judge these sites are not yet ready for randomized studies. Optimizing proton RT with scanned beams, delineating and controlling target position, finely determining end-of-range, and robust intensity modulation can improve target dose conformity, maximizing local tumor control. We seek to optimize IMPT using investigational biophysical tools. We will also explore modulation of the LET distribution with scanned protons for radiobiologic advantage in a phase I clinical study in CNS malignancies. This project supports the mission of the NCI to improve the treatment and continuing care of cancer patients.