Project Summary Radiotherapy (RT) aims to deliver tumoricidal dose to clinical target volume (CTV) while sparing organs at risk (OAR), for which proton and photon beams are naturally complementary to each other: protons are generally better for OAR sparing, while photons are more robust to delivery uncertainties for CTV coverage. The hybrid proton-photon RT has a long history. However, as it generates proton and photon plans separately without fully utilizing joint proton-photon optimization during the planning stage, current hybrid RT is pseudo- hybrid and very limited in plan quality, treatment sites, and broad applicability. The key to leapfrog from pseudo-hybrid to truly-hybrid RT is new joint proton-photon optimization method that synergizes complementary proton and photon beams. The hypothesis is that truly-hybrid RT via appropriate joint proton- photon optimization will be more favorable than proton or photon-only RT, in terms of CTV coverage robustness and OAR sparing optimality. Broad applicability of truly-hybrid RT to patients: (A) Clinical applicability: unlike pseudo-hybrid RT that is limited in plan quality and treatment sites, truly-hybrid RT may become a new paradigm for general cancer RT, owing to its superior plan quality and thus potentially clinical outcomes to proton-only or photon-only RT. (B) Clinical workflow: our truly-hybrid plans can be individually and safely delivered on existing proton and photon machines, and this effort envisions patients being treated in an integrated cancer center like ours with both proton and photon equipment, under the direction of a single physician, using shared immobilization devices, simulation procedure and structure set, and integrated treatment planning and delivery system. (C) Patient coverage: truly-hybrid RT can be made broadly available to many cancer patients through existing infrastructures in US, since (1) most hospitals with proton centers also have photon centers; (2) 76% of cancer patients live in the states with operational proton centers, while 85% are within 100-mile (2-hour-driving) distances to these proton centers; (3) cancer patients are more willing to travel for advanced treatment options. Proposed effort: Inspired by unprecedented plan quality and broad applicability of truly-hybrid RT via our joint proton-photon optimization method, the next step is to test the hypothesis prospectively via clinical trials. However, a missing prerequisite to advance truly-hybrid RT from research to clinic is a treatment planning system (TPS) that can generate clinically-deliverable hybrid plans. To meet this urgent need, this effort will develop novel optimization methods and TPS for clinically-deliverable truly-hybrid RT, which is a radical step towards prospective clinical trials for testing the hypothesis. Aim 1: Optimization methods and TPS for clinically-deliverable truly-hybrid RT. Aim 2: Optimization methods for accurate and efficient MCO truly-hybrid planning. Aim 3: De...