## 4 Discussion
The results in this study, generally consistent with published results in literature, show that HU variations due to contrast materials were statistically significant (\(p\)-value \(<0.05\)) for the majority of critical structures and target volumes. However, this did not imply clinical significance since the variation in HU values were within 30 HU for the vast majority of soft tissue and less than 50 HU for lungs and bony structures. Variation in PTV ICRU 83 recommended dose metrics D\({}_{2\%}\) and D\({}_{98\%}\) values were statistically insignificant for all sites except for brain and nasopharynx, even though, these statistical differences did not result in clinically significant dose metric differences between NCCT- and CCT-based plans, because difference in D\({}_{2\%}\) and D\({}_{98\%}\) values were less than 2% (see Tables 6 and 7). In this study, 3D gamma analysis using local dose comparison method was applied to compare all dose distributions point by point. Unlike global difference point, local comparison is more sensitive to differences in dose calculations [43]. The 3D gamma analysis results revealed that 94% of plans satisfied the recommended 2% and 2 mm criteria, and only 6% of all plans failed the criteria. All 226 patients' plans, however, satisfied the 3% and 3 mm criteria. Gamma evaluation failures in the 14 patients is attributed to uncontrollable changes in patients' geometry due to involuntary movements in the lag time between NCCT and CCT scans. Respiratory-induced differences were observed in eight nasopharyngeal patients, one thyroid, and one esophagus cancer patient. Bowel movement-induced differences were observed in two rectum patients, one uterus, and one cervix cancer patient. Two examples for geometry changes are shown in Figure 7; gamma passing rates were reduced because of small movement in body parts and penile displacement in subset A and respiratory movement in subset B. It should be noted that in all treatment plans that did not satisfy the 2% and 2 mm criteria, the dose differences were in low dose regions only which are not clinically significant, and therefore increasing the suppression threshold to 20% was enough to score a satisfactory gamma pass rate with the 2% and 2 mm criteria. We have evaluated the effect of contrast materials in clinical radiation oncology relevant setups to provide a credible clear answer on the utilization of contrast enhanced CT-simulation images for dose calculation. Due to their chemical composition, contrast material densities are often overestimated in CT images, which might lead to inaccurate dose calculations. Despite this, the results demonstrated a limited effect of distorted CCT images on dose calculations mainly because radiation doses in modern radiotherapy are usually delivered through several fields and arcs, and the fact that changes on CT number of an order of several HU has limited effect on dose calculation. In addition, contrast materials are confined to blood vessels in case of intravenous administration, or to the digestive track if administered orally. Apparently, it is the artefacts induced by contrast agents rather than the minute concentrations that interfere with CT numbers.