## 1 Introduction  
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death world-wide in 2020, with approximately 906,000 new cases and 830,000 [1]. Rates of both incidence and mortality are 2 to 3 times higher among men than among women in most regions and liver cancer ranks fifth in terms of global incidence and second in terms of mortality for men [1]. The global estimated average incidence to mortality ratio is 1.07 for men and 1.06 for women [2] and the disease burden attributable to this cancer induces a substantial number of years of life lost [3]. Consequently, due to its extremely aggressive nature and poor survival rate [4], it represents an important public health issue worldwide. The management of this disease is determined after stratification into three groups: (I) resectable; (II) unresectable or medically inoperable; and (III) metastatic. Unfortunately, the majority (50-90%) of liver cancer patients present with unresectable disease [5; 6]. In these situations, multimodality management with a combination of radiation oncology, medical oncology, surgical oncology, and interventional radiology is crucial. Over the last years, therapy with \({}^{90}\)Y-labeled microspheres has gained widespread acceptance as a safe and effective technique for treating hepatocellular carcinoma (HCC) and metastatic liver malignancies with a growing number of ongoing trials. This therapeutic option is also known as radioembolization (RE). During RE \({}^{90}\)Y-laden microspheres are injected directly within the tumor through the hepatic artery and become trapped at the precapillary level delivering a potentially tumoricidal dose to the target tumor while sparing surrounding normal parenchyma, thereby permitting a selective delivery of the microspheres [7; 8]. \({}^{99m}\)Tc-labeled macroaggregated albumin (\({}^{99m}\)Tc-MAA) has been largely used as a surrogate radiopharmaceutical for treatment planning. The underlying assumption is that \({}^{99m}\)Tc-MAA biodistribution simulates the expected microsphere delivery during \({}^{90}\)Y radioembolization. Since the inception of the therapy, planar imaging using \({}^{99m}\)Tc-MAA has been successfully used to assess the lung shunt fraction and to estimate the absorbed dose to lungs after \({}^{90}\)Y RE treatment. Of note, the assessment of extrahepatic shunting is particularly important in the case of primary disease, as lung shunting fraction exceeding 20% has been observed for HCC [9]. With the advent of hybrid SPECT/CT systems, \({}^{99m}\)Tc -MAA administration before therapy has begun to be used to obtain in vivo quantitative information on the estimated microsphere biodistribution following the therapeutic administration. Furthermore, when used in conjunction with dosimetry models, \({}^{99m}\)Tc-MAA biodistribution may provide estimated absorbed doses both to lesions and liver parenchyma. In fact, absorbed doses estimates can be mathematically determined by converting quantitative \({}^{99m}\)Tc-MAA SPECT data to the absolute \({}^{90}\)Y activity and then converting these values to absorbed doses estimates using the available dose calculation algorithms (e.g., MIRD [10], partition [11], kernel convolution [12; 13] or local deposition models [12; 13]). The consensus is that SPECT/CT-based dosimetry is superior to planar scintigraphy by tomographically resolving overlapping radiotracer activity, evaluating heterogeneous radiotracer uptake, and detecting activity in small lesions [14]. In addition, several phantom studies have shown that \({}^{99m}\)Tc-MAA SPECT/CT volume measurements are accurate and reproducible, although additional measurements on patient-like phantoms are needed [15; 16]. Recent evidence suggests that the combination of anthropomorphic phantoms with quantitative software (such as xSPECT or Hermes SUV-SPECT software) could represent a major step forward in improving image accuracy and predictability of therapy planning [17].