## 4 Discussion  
Several authors have been studying the accuracy of SPECT-MAA dosimetry to predict response, clinical impact, and outcomes for selected patients [14; 30; 39; 51]. Others have been developing individualized treatment planning dosimetry strategies introducing radiobiology concepts [44; 52; 53]. To the best of our knowledge, while several dosimetric and clinical evaluations are reported in the literature, the optimization of \({}^{90}\)Y activity to be administered based on patient-specific pre-treatment SPECT-MAA ADD together with the imposition of AD thresholds at the level of PTV and NLV voxels has never been addressed. Moreover, the recent European Council Directive 2013/59/EURATOM explicitly recommends that medical exposures shall be individually planned and optimized [19]. To address these important issues, there is a need to first validate the dosimetry methodology based on ground truth data. For this purpose, we have built our own phantoms with similar volumes for NLV and desire PTV and known activities of \({}^{99m}\)Tc-MAA and \({}^{90}\)Y-MS. Our phantom studies revealed a strong correlation and agreement between the voxelwise ROI values in the simulated liver and PTV cylinders obtained from the SPECT-MAA- and PET-MS-based ADD. The results regarding the two derived ADD (i.e., one respect to the other) do not provide information about their accuracy with respect to the actual ADD known from the phantom distribution ground truth (i.e., real activity concentration in phantom). Considering the phantom studies, the derived ADD in the biggest cylinder volume of 108 mL accuracy for the SPECT-MAA and PET-MS showed an acceptable error (<8%) from the ground truth distributions. On the other hand, and most probably mainly due to the partial volume effect amongst the others, the 8 mL and 15 mL volumes showed an error of approximately 50% from the ground truth distributions, indicating sub-optimal derived ADD estimation. These observations require careful evaluation whenever derived ADD in less than 100 mL PTV must be considered. Even though, in our patient sample, all the ROI mean AD estimated post-treatment agreed well with the pre-treatment calculations. So far, and concerning the activity optimization methodology, we found optimal values estimated with pre-treatment SPECT-MAA to agree well with optimal activity estimated in the post-treatment PET-MS in eleven treatments. In five treatments, the optimal activity estimated based on the SPECT-MAA and PET-MS did not converge in the range defined as acceptable (0-12 GBq). In two out of these five treatments, the disagreement observed was possibly due to a discrepancy in the exact site of MAA and MS intra-arterial administrations in the liver. For the other three treatments, the OF optimization did not converge within the range of defined activities. The main reason for this behavior is likely to be due to the highly selective distribution within the PTV (for both MAA and MS administrations) that spared the NLV. This means that, in these specific cases, the administered activity might have been higher than it was, with no significant damage to the NLV. In five out of the eleven treatments (see Table 4), the administered activity was lower, i.e., 33% to 68%, than the estimated optimal activity. In four of these (P3_3, P4_5, P7_8, P12_14), the PTV was larger than 100 mL. In this regard and according to our phantom studies, it is highly likely that the accuracy of the measurements in these patients' PTV is very high, and therefore the administered activities might have been optimized/higher. All these previous considerations assume the accepted threshold herein imposed (<70 Gy in NLV and >80 Gy in PTV) to be practical and an adequate \"rule of thumb\" to salvage NLV when delivering enough of a dose to PTV. These reference thresholds deserve adequate adjustments for each patient-specific condition. As we described previously, we have addressed this issue by successfully testing the OF behavior for several pairs of thresholds.