Systems, methods, and related computer program products for medical imaging and image-guided radiation treatment (IGRT) are described. In one preferred embodiment, an IGRT system provides intrafraction target tracking based on a comparison of intrafraction x-ray tomosynthesis image data with initial x-ray tomosynthesis image data acquired with the patient in an initial treatment position, the initial x-ray tomosynthesis image data having an inherent registration with co-acquired image data from a setup imaging system integral with, or having known geometry relative to, the tomosynthesis imaging system. Repeated registration of intrafraction x-ray tomosynthesis image data with pre-acquired reference image data from a different frame of reference is not required during intrafraction radiation delivery. Advantages include streamlined intrafraction computation and/or reduced treatment delivery margins.
