An adaptive radiation therapy delivery system, comprising: a therapy generator configured to deliver a therapy beam to be directed to a therapy locus; and a therapy controller system coupled to the therapy generator, the therapy controller system comprising an imaging input, the therapy controller system configured to perform operations comprising: receiving an inter-fractional volumetric image comprising a time-varying target locus, the inter-fractional volumetric image acquired at a first time period; receiving at least two intra-fractional imaging slices comprising different portions of the target locus, wherein a first intra-fractional imaging slice is acquired at a second time period and a second intra-fractional imaging slice is acquired at a third time period, wherein the at least two intra-fractional imaging slices are received contemporaneously with a radiation therapy delivery session and are in different image planes having different orientations; spatially registering a portion of the target locus from the first intra-fractional imaging slice and a portion of the target locus from the second intra-fractional imaging slice, including translating the portion of the target locus in the second intra-fractional imaging slice to register the portion of the target locus in the second intra-fractional imaging slice with the portion of the target locus in the first intra-fractional imaging slice; determining a difference between a location of the target locus indicated by the spatially-registered information and the target locus indicated by the inter-fractional volumetric image; and generating an updated therapy protocol to control delivery (1310, 1312) of a therapy beam based on the determined difference. a therapy generator configured to deliver a therapy beam to be directed to a therapy locus; and a therapy controller system coupled to the therapy generator, the therapy controller system comprising an imaging input, the therapy controller system configured to perform operations comprising: receiving an inter-fractional volumetric image comprising a time-varying target locus, the inter-fractional volumetric image acquired at a first time period; receiving at least two intra-fractional imaging slices comprising different portions of the target locus, wherein a first intra-fractional imaging slice is acquired at a second time period and a second intra-fractional imaging slice is acquired at a third time period, wherein the at least two intra-fractional imaging slices are received contemporaneously with a radiation therapy delivery session and are in different image planes having different orientations; spatially registering a portion of the target locus from the first intra-fractional imaging slice and a portion of the target locus from the second intra-fractional imaging slice, including translating the portion of the target locus in the second intra-fractional imaging slice to register the portion of the target locus in the second intra-fractional imaging slice with the portion of the target locus in the first intra-fractional imaging slice; determining a difference between a location of the target locus indicated by the spatially-registered information and the target locus indicated by the inter-fractional volumetric image; and generating an updated therapy protocol to control delivery (1310, 1312) of a therapy beam based on the determined difference. receiving an inter-fractional volumetric image comprising a time-varying target locus, the inter-fractional volumetric image acquired at a first time period; receiving at least two intra-fractional imaging slices comprising different portions of the target locus, wherein a first intra-fractional imaging slice is acquired at a second time period and a second intra-fractional imaging slice is acquired at a third time period, wherein the at least two intra-fractional imaging slices are received contemporaneously with a radiation therapy delivery session and are in different image planes having different orientations; spatially registering a portion of the target locus from the first intra-fractional imaging slice and a portion of the target locus from the second intra-fractional imaging slice, including translating the portion of the target locus in the second intra-fractional imaging slice to register the portion of the target locus in the second intra-fractional imaging slice with the portion of the target locus in the first intra-fractional imaging slice; determining a difference between a location of the target locus indicated by the spatially-registered information and the target locus indicated by the inter-fractional volumetric image; and generating an updated therapy protocol to control delivery (1310, 1312) of a therapy beam based on the determined difference.