Purpose: This research aims at quantifying the extent of potential therapeu-tic gain that can be achieved from altering the radiation dose distribution overtreatment sessions in fractionated radiotherapy. Methods: A spatiotempo-rally integrated planning approach is developed, where the spatial and tempo-ral dose modulations are optimized simultaneously. The concept ofgeneralized equivalent uniform biologically effective dose (EUBED) is usedto quantify and compare the clinical quality of spatiotemporally heteroge-neous dose distributions in target and critical structures. This gives rise to alarge-scale non-convex treatment-plan optimization problem, which is solvedusing global optimization techniques. The spatiotemporally integratedapproach is used to design plans that deliver distinct dose distributions overtreatment sessions. The plans are compared against those obtained using tra-ditional equivalent uniform dose (EUD)-based planning methods that onlyallow for time-invariant dose distributions.