Objectives and Specific Aims Any tumor cell can be eradicated with a sufficiently high dose of radiation;conversely, any normal tissue can be injured with sufficient dose to a given volume. The challenge for clinicians is to deliver the appropriate dose to only those tissues containing tumor. Proton radiation fields, with no exit beyond the target, deliver less radiation to normal tissues than comparable photon (x-ray) fields. This improves the therapeutic ratio (of cure probability to complication risk) because irradiation of normal tissue does not benefit the patient. We have treated nearly 7,000 cancer patients with proton therapy at the Harvard Cyclotron and Francis H. Burr Proton Therapy Center (FHBPTC) since 1974. We have achieved significant gains in clinical outcomes for a number of disease sites including chondrosarcomas and chordomas of the skull base and cervical spine (95% and 50% local control, respectively), paranasal sinus tumors (82% local control), ocular melanoma (97% local control), and prostate cancer (80% biochemically disease-free). At the FHBPTC, we have been able to expand the range of diseases treated to include pediatric malignancies at nearly any anatomic site including craniospinal axis treatment under anesthesia, nasopharyngeal carcinoma, lung and hepatocellular tumors under respiratory gating, and pelvic and retroperitoneal sarcomas. We believe that research in this field can further iimprove our utilization of the proton beam in the clinic to enhance treatment outcome. We hypothesize that, mainly through the use of advanced imaging technology, we can deliver higher precision proton therapy to further improve target coverage and/or reduced dose to nearby critical structures. We propose 3 integrated projects (1)Clinical Utilization of the Physical Advantages of Proton Therapy, (2)Optimizing the Use of Protons in the Clinic, and (3) Morbidity Reduction with Proton Radiation Therapy to test this hypothesis. The specific aims of the projects are to develop dose guided proton therapy techniques including PET/CT imaging to measure the activation of positron emitters through the proton beam, to control range in the presence of organ motion, and to advance beam delivery strategies for intensity modulated proton therapy to further improve therapeutic ratio. In selected clinical sites where tumor closely invests normal tissue, morbidity reduction with targetted biologic agents will also be explored.