Background: PSMA-based alpha therapy using 225Ac-PSMA-I&T provides treatment for metastatic castration-resistant prostate cancer (mCRPC), even after the failure of 177Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcomes and plays an increasing role in mCRPC patients. Hence, we aimed to assess TTV and its changes during 225Ac-PSMA-I&T RLT. Methods: mCRPC patients undergoing RLT with 225Ac-PSMA-I&T with available 18F-PSMA-1007 PET/CT prior to therapy initiation were included. TTV was assessed in all patients using established cut-off values. Image derived, clinical and biochemistry parameters (PSA, LDH, AP, pain score) were analyzed prior to and after two cycles of 225Ac-PSMA. Changes in TTV and further parameters were directly compared and then correlated with established response criteria, such as RECIST 1.1 or mPERCIST. Results: 13 mCRPC patients were included. The median overall survival (OS) was 10 months. Prior to 225Ac-PSMA RLT, there was no significant correlation between TTV with other clinical parameters (p > 0.05 each). Between short-term survivors (STS, p = 0.592 & p = 0.286, respectively), whereas AP was significantly lower in the LTS (p = 0.029). A total of 7/13 patients completed two cycles and underwent a follow-up 18F-PSMA-1007 PET/CT. Among these patients, there was a significant decrease in TTV (median 835 vs. 201 mL, p = 0.028) and PSA (median 687 ng/dL vs. 178 ng/dL, p = 0.018) after two cycles of 225Ac-PSMA RLT. Here, percentage changes of TTV after two cycles showed no direct correlation to all other clinical parameters (p > 0.05 each). In two patients, new PET-avid lesions were detected on 18F-PSMA-1007 PET/CT. However, TTV and PSA were decreasing or stable. Conclusion: PET-derived assessment of TTV is an easily applicable imaging biomarker independent of other established parameters prior to 225Ac-PSMA RLT in these preliminary follow-up data. Even after the failure of 177Lu-PSMA, patients with extensive TTV seem to profit from RLT. All but one patient who was eligible for ≥2 cycles of 225Ac-PSMA-RLT demonstrated drastic TTV decreases without direct correlation to other biomarkers, such as serum PSA changes. Changes in TTV might hence improve the response assessment compared to standard classifiers by reflecting the current tumor load independent of the occurrence of new lesions.
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