## 4 Discussion
### Strengths and Weaknesses  
Several strengths can be acknowledged in this study. The most important of them is that, to the best of our knowledge, this is the first study investigating the feasibility of such an approach in synergy with and not in substitution for traditional image guidance procedures. Secondly, this approach has been tested in a cohort of pediatric patients treated with HT, for whom reduction in treatment time and imaging dose is of paramount importance. Despite being innovative in nature, the study presents some limitations worth addressing. First of all, the sample size is relatively small, compared to other studies in the literature involving a higher number of patients. However, while these studies consider an adult population and conventional photon RT, the present investigation only selects pediatric patients treated with HT. Additionally, for each patient, an average of 27 fractions was available, meaning more than 850 fractions and 5000 coordinates, making the results robust enough from a statistical point of view. Another limitation is represented by the heterogeneity of the population in terms of age range. As a matter of fact, despite all patients included in the study being classified as pediatrics, some of them can be classified as adolescents and young adults (AYA), according to the definition of the European Society for Pediatric Oncology (SIOPE) (siope.eu), their age range being between 2 and 28 years old. Furthermore, some younger patients were treated in narcosis, others with thoracic malignancies in gating. Analogously, anatomical districts treated ranged widely, including head and neck, thorax and pelvis, and it is well-known that pelvic treatments are associated with much larger CVs compared to head and neck treatments, due to higher variability in patient's anatomy. Regarding narcosis, no evident and definitive conclusions can be drawn, as witnessed by the absence of a clear trend of CVs for these patients (Table 1). As anticipated, there should be systematic sources of misalignments along the treatment path. For instance, as reported by a previous investigation considering patients treated at our Institution [6], the observed trend in the antero-posterior (z) direction can be explained by the deformation of thermoplastic masks, patient relaxation between simulation and subsequent treatment fractions, and target movement with respect to bony landmarks for pelvic treatments. In addition, the treatment isocenter is defined relative to CT couch which, differently from the treatment couch, does not include weight compensation. The increase in pediatric patients treated at our Institution will enable us to enlarge the cohort and stratify patients by age, pathology and narcosis. Besides this, the methodology can be easily tested considering also an adult population, so that the cohort can be further expanded. From a methodological standpoint, the performances of the algorithm were evaluated exclusively in terms of a reduction in the magnitude of the CV, which was computed as the Euclidean norm of the CV itself. Despite being a synthetic and complete index, the norm of a vector, per definition, does not allow us to discern variations of the single components. In other words, it is not straightforward to assess to which coordinate a reduction or an increase of the magnitude of the CV is imputable. Nevertheless, the study has demonstrated that correcting translational coordinates, especially in the posterior-anterior direction, is significantly more impactful than correcting rotational components only. Another aspect that should be carefully considered is the difference in the imaging system between the lateral rooms (rotating stereoscopic, isocentric) and the central one (robotic, off-iso). The limited dataset does not allow us to derive definitive conclusions on whether the difference in the imaging systems may cause variations in the performance of the algorithm.