# The Role of PET and SPECT Imaging in Prostate Cancer Targeted Alpha Therapy: When and How?
## 6 Discussion  
TAT holds the promise to represent a powerful weapon in oncology, especially as far as it concerns the management of mCRPC. However, it has to be highlighted that to date, \({}^{223}\)Ra therapy is the first and only alpha-emitter agent approved by the regulatory authorities (i.e., FDA and EMA) for therapeutic use. It is noteworthy that TAT is not something new in the history of nuclear medicine, since many decades of research on alpha-emitters paved the way for the implementation of such a therapeutic regimen in clinical practice [106]. In 2018, according to a specific note issued by the EMA (EMA/500948/2018) on the indications for \({}^{223}\)Ra therapy in a review of an ongoing phase 3 trial by the EMA's Pharmacovigilance Risk Assessment Committee, \({}^{223}\)Ra therapy was practically placed as a third-line therapy in mCRPC management. This indication led to the enrollment of heavily pre-treated patients, bearing high tumor burden metastatic disease, in contrast with published data showing a relatively more favorable outcome in subjects with lower metabolic tumor volume at baseline [55, 107]. From this perspective, an accurate patients' stratification before TAT enrollment plays a crucial role [108]. The amazing therapeutic success of \({}^{225}\)Ac-PSMA-617 in the treatment of mCRPC reported in recent papers has greatly increased interest in the clinical use of targeted alpha therapy. The use of \({}^{225}\)Ac-PSMA-617 highlights the potential applicability of the idea of targeted alpha treatment in cancer and offers a viable therapeutic alternative for prostate cancer [74]. Most of these agents are still in the preclinical phase of investigation, and \({}^{213}\)Bi-PSMA is one of the few to have been tested clinically with no definitive results. However, the possibility to use different alpha emitters labeled with PSMA moleculesand antibodies, which present different half-lives and physical properties, may open a new chapter of the prostate cancer management, especially considering the novel trends in TAT combination therapies, which are already described in the clinical setting for the combination \({}^{177}\)Lu-PSMA/\({}^{225}\)Ac-PSMA therapy [78; 79; 80]. Beyond the evidence that supports the introduction of PSMA-based TAT in the therapeutic schema of mCRPC, there is a need for clinical trials to better define the timing of the application of \({}^{225}\)Ac-PSMA in the treatment sequence of mCRPC [63]. In fact, the results are not heterogeneous and, according to some authors, the risk of a shorter progression-free survival in PSMA-based TAT exists in patients already treated with \({}^{177}\)Lu-PSMA, suggesting that prior beta-emitter therapy may induce resistance to radiation [109]. As more centers gain access to \({}^{225}\)Ac-PSMA, more data are becoming available. To our knowledge, we could not find a clinical study that includes the bone scan in the PSMA-based TAT management and therapy assessment algorithm. Of course, the bone scan may provide information concerning the bone involvement, but for PSMA-based TATA, therapeutic planning seems not mandatory: the only useful aspect of bone scan regarding the TAT is the superscan findings, which can be provided by different and more specific methodologies [84]. Imaging professionals have been forced to adapt and develop techniques or algorithms for reporting follow-up imaging as a result of the increase and extension of the use of PSMA-based ligands in imaging and therapy. Particularly in cases of bone-dominant illness, the molecular response evaluation is preferred above morphological response criteria in individuals with mCRPC. Actually, the PSMA PET/CT imaging criteria is considered the dominant tool for the patient's selection and for PSMA-based TAT monitoring, allowing also the classification of patients as responders, stable disease, and non-responders [86].