## 4 Discussion  
The presence of contrast agents in the body and the resulting distortions are clearly visible in planning CT images. It is a valid inquisitive point when radiotherapy treatment planning accuracy is in question. A direct result for this concern is reflected in common radiation therapy practice of twin CT image acquisition, NCCT and CCT, which is associated with inconvenience to the patient and added cost. In addition, published work presents inconsistent findings, making it even more challenging to quantify the practical significance of the resultant dosimetric effect in a clinical sense. In this study, we have demonstrated the extent of the effect of contrast materials on CT images in terms of HU and the magnitude of the consequential dosimetric effect in clinically relevant setups. This study also involved a larger number of patients compared to previous studies and included all major cancer treatment sites in contrast to site-specific studies. In addition, other factors affecting the quality of the statistical analysis were addressed in this study, such as registration effects, which have been rarely mentioned in previously published studies. Published studies that evaluated the effect of contrast agents on radiotherapy dose calculations have discussed conventional radiotherapy, 3 DCRT, IMRT, and, more recently, VMAT, see Table 1. These studies can be grouped into two main categories: the first one is based on phantoms and mathematical models, the second is based on clinical CT images. Studies in the first category lean toward simulating clinical observations based on the amount of contrast material and beam energy; results generally tend to emphasize the apparent significant effect of contrast material rather than the clinical effect [13; 16; 17]. While studies in the second category generally place emphasis on clinical outcome and reported dose, differences were mostly within clinically acceptable limits. The results of reviewed literature, summarized in Table 1, indicate that the majority of studies suggest clinically insignificant effect of contrast agents on radiotherapy dose calculations for both critical structures and target volumes. However, conclusions are usually conservative and recommend the use of NCCT images or applying density corrections. Many other authors, however, reported considerable discrepancies between dose calculations based on NCCT and CCT image sets. [PERSON] et al. [16] reported a significant effect on the planning of upper-abdominal irradiation as MU was increased over 2%. [PERSON] et al. [17] reported a statistically significant dose difference in the lower esophageal region target volume. [PERSON] et al. [30] also reported statistically significant dose differences between NCCT- and CCT-based plans for both target volumes and critical  
Figure 6: 3D gamma index pass rate for the all sites with criteria 2 mm/2% and 3 mm/3%. structures. [PERSON] et al. [20] concluded that oral contrast agents caused clinically significant changes in the dose calculations for the targets and critical structures. [PERSON] et al. [13] reported significant dose discrepancy for critical structures, and [PERSON] et al. [34] found a considerable increase in MU settings due to contrast agents presence in CCT images. The results in this study 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 dose metrics D\({}_{2\%}\) and D\({}_{98\%}\) values were clinically insignificant for all sites except for brain and nasopharynx. Relative dose maximum differences were within 2% for the majority of critical structures. Similarly, in target volumes, minimum, maximum, mean, and median values for D\({}_{2\%}\) and D\({}_{98\%}\), were within 1.5%.