## 4 Discussion
### Comparison with Previous Investigations  
The statistics of the shifts herein presented are in line with the published literature and with the ones already reported by our group in a previous study [6], according to which extracranial treatments are associated with higher systematic errors and lower relative SD, making them the perfect candidates for such a pre-correction approach. The reported shifts highlight the need to improve the patient positioning procedures, even if corrections are overall quite modest and in line with the published literature. Accordingly, the first counteraction is to analyze the causes that contribute to the systematic error, in order to mitigate those related to human factors. Performing separate analyses on the dependence of results on inter-operator variability could help to shed a light on this aspect, provided that a larger cohort needs to be considered to derive robust and statistically significant results. Once one has minimized the human-related factors that contribute to setup errors, the described procedure can be streamlined in the clinical pipeline to assist positioning procedures. In the literature, several studies exist that explore the potential of such pre-alignment protocols to be used in the substitution of image-guidance in conventional photon RT [16]. As a matter of fact, in conventional RT, this strategy could represent an alternative to in-room image-based setup verification from a certain fraction on. On the contrary, the steep dose gradients that characterize HT make IGRT a prerequisite, and such a strategy cannot entirely replace daily imaging for patient verification. However, refining patient position before imaging is useful also in HT, because faster setup procedures improve patient's experience, reduce intra-fractional movement, increase patients' throughput and in principle reduce the frequency of imaging and related dose [17]. Therefore, although image-guided patient verification remains somewhat mandatory over the whole course of treatment due to the high geometric selectivity of particles, the implementation of such a strategy could help to improve the clinical workflow, by reducing overall treatment time and decreasing imaging dose to the patients. First of all, reducing significantly the entity of CV has the potential to decrease time associated with daily image registration procedures, the kV images being closer to the DRRs. Practically, in CNAO, the manual registration phase that precedes the automatic one could be skipped if the images to match are closer. Secondly, the application of smaller CVs makes the clinician more confident about the fact that the final position of the patient is reached correctly, and prevents further verification. As anticipated, significant shifts (i.e., rotations > 2 degrees) might affect setup and could require a second imaging or re-positioning based on clinical decision. The results demonstrate that, for most patients and treatment fractions, this pre-correction strategy would have been successful, as the magnitude of the CV was reduced. However in some cases, it led to a worsening of the situation, with the patient being virtually moved even farther from the treatment isocenter before imaging. Further investigations are therefore necessary to select the patient categories more likely to benefit from such an approach. One could expect later fractions to be associated with lower values of normalized norms, i.e., that the greater the number of fractions completed, the more information is available, and the more effective the pre-correction strategy. Instead, no clear trend can be observed in these data, and this can be explained by the inhomogeneity of the patients' cohort in terms of age and the inter-observer variability intrinsic in the methodology. The proposed method could benefit from the identification of action levels, as described by [PERSON] and Colleagues [15].