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The aim of this work is to investigate in-room proton radiographies to compensate realistic rigid and non-rigid transformations in clinical-like scenarios based on 2D–3D deformable image registration (DIR) framework towards future clinical implementation of adaptive radiation therapy (ART). Monte Carlo simulations of proton radiographies (pRads) based on clinical x-ray CT of a head and neck, and a brain tumor patients are simulated for two different detector configurations (i.e. integration-mode and list-mode detectors) including high and low proton statistics. A realistic deformation, derived from cone beam CT of the patient, is applied to the treatment planning CT. Rigid inaccuracies in patient positioning are also applied and the effect of small, medium and large fields of view (FOVs) is investigated. A stopping criterion, as desirable in realistic scenarios devoid of ground truth proton CT (pCT), is proposed and investigated. Results show that rigid and non-rigid transformations can be compensated based on a limited number of low dose pRads. The root mean square error with respect to the pCT shows that the 2D–3D DIR of the treatment planning CT based on 10 pRads from integration-mode data and 2 pRads from list-mode data is capable of achieving comparable accuracy (∼90% and &gt;90%, respectively) to conventional 3D–3D DIR. The dice similarity coefficient over the segmented regions of interest also verifies the improvement in accuracy prior to and after 2D–3D DIR. No relevant changes in accuracy are found between high and low proton statistics except for 2 pRads from integration-mode data. The impact of FOV size is negligible. The convergence of the metric adopted for the stopping criterion indicates the optimal convergence of the 2D–3D DIR. This work represents a further step towards the potential implementation of ART in proton therapy. Further computational optimization is however required to enable extensive clinical validation.

X-ray CT adaptation based on a 2D–3D deformable image registration framework using simulated in-room proton radiographies