Abstract: A system comprises a therapy tasks scheduling module (30) constructing a workflow schedule for performing a plurality of therapy tasks including dose optimizations, and a dose optimization module (26) performing a dose optimization in accordance with the workflow schedule to generate a therapy plan. The dose optimization module performs inverse radiation therapy planning that iteratively adjusts (82) a set of radiation therapy parameters (70) to optimize a simulated spatial dose distribution (72) respective to a set of radiation therapy objectives (78). In some embodiments, at least some iterations update a region of a fluence map that is smaller than the entire fluence map. In some embodiments, at least some iterations optimize the simulated spatial dose distribution respective to a subset of the set of radiation therapy objectives. In some embodiments, the simulated spatial dose distribution has a nonuniform voxel size.