## 4 Discussion
### Dose-Survival Relationship  
The number of studies reporting a relationship between response and tumor dose are increasing over time for patients treated with TARE. Specifically concerning \({}^{90}\)Y-loaded resin microspheres, a threshold of 100-120 Gy as a predictor of treatment response or OS has been identified by several studies [27]. In this context, therefore, the cutoff reported in the cohort of patients investigated in this study was in agreement with other authors [7; 28; 29; 30]. In detail, [PERSON] et al. reported a significantly higher mean target-absorbed dose of 99 Gy in patients with complete or partial tumor response using \({}^{90}\)Y-bremsstrahlung SPECT [30]. [PERSON] et al. [28] reported a TD of 92 Gy for predicting the complete or partial tumor response. In a much smaller series, all patients who showed a response after resin microsphere treatment had received a tumor dose of at least 91 Gy [29]. Moreover, [PERSON] et al. [7] reported a cutoff in terms of the target mean absorbed dose of 115 and 98 Gy, using \({}^{99m}\)Tc-MAA SPECT/CT- and \({}^{90}\)Y PET/CT-based dosimetry, respectively, for predicting the OS. Of note, the methodology proposed in this paper for the evaluation of the impact of VOI transfer can also be applied to images from TARE patients treated with \({}^{90}\)Y-loaded glass or \({}^{166}\)Ho-PLLA microspheres. It should be noted, nevertheless, that the cutoffs of mean absorbed dose used for stratifying survival curves reported in this study are only applicable to \({}^{90}\)Y-loaded resin microspheres as the tumor mean absorbed doses that are needed to treat the patients depend on the characteristics of the used device (e.g., the specific activity per microsphere, the dose rate, the heterogeneity of the absorbed dose distribution and the embolization capability) [31; 32]. In particular, these characteristics led to reported threshold doses ranging from 205 Gy to 257 Gy for various tumor types treated with \({}^{90}\)Y-loaded glass microspheres [27] and 90 Gy for colorectal cancer metastasis treated with \({}^{166}\)Ho microspheres [33]. In addition, the role of \({}^{99m}\)Tc-MAA should be carefully considered when compared to \({}^{90}\)Y-loaded resin/glass microspheres, due to the intrinsic differences in terms of shape, size, size variability, density and number of injected particles [20]. Moreover, there are differences in the image-based activity quantification when comparing the \({}^{99\text{m}}\)Tc-MAA SPECT/CT and \({}^{90}\)Y PET/CT activity distributions. Both issues could partially explain the disagreement between pre- and post-treatment absorbed dose distributions reported in this study. These limitations could be overcome in \({}^{166}\)Ho-loaded microsphere TARE, where a superior predictive value of \({}^{166}\)Ho scout dose for intrahepatic distribution with respect to \({}^{99\text{m}}\)Tc-MAA was reported [34]. Nevertheless, the replication of the angiographic procedure simulated with the \({}^{99\text{m}}\)Tc-MAA or \({}^{166}\)Ho scout dose during the treatment still plays a critical role for the pre- and post-treatment absorbed dose distribution agreement [35]. A limitation of this study is that the post-treatment dosimetry image is optimized according to 2020 Hou, indicating 4000 as the optimal beta value for dosimetric purposes. Nevertheless, the results of the impact of VOI propagation remain generally applicable to reconstructed images. Of note, in all the patients we used the same \({}^{99\text{m}}\)Tc MAA SPECT/CT acquisition and reconstruction protocol. Another issue is that the VOI propagation algorithm previously validated in [PERSON] et al. [25] is only based on the CT images of both SPECT/CT and PET/CT. In particular, we recognize that the hybrid CT has a poor image quality when compared to CECT but it is still able to capture the mechanical deformation of the liver that occurs between SPECT/CT and PET/CT image acquisitions due to patient breathing and positioning.