Outcome-driven dosimetry optimization for [177Lu]Lu-PSMA-617 radiopharmaceutical therapy: proof of concept on single time point dosimetry optimization

Abstract Purpose Internal dosimetry in radiopharmaceutical therapy (RPT) traditionally prioritizes methodological optimization driven by physical dose accuracy. However, even recommended multiple-time-point (MTP) dosimetry remains subject to uncertainties related to limited sampling schedules, pharmacokinetic, and curve-fitting modeling assumptions. In patients with metastatic castration-resistant prostate cancer (mCRPC) treated with [ 177 Lu]Lu-PSMA-617 RPT, we explored an outcome-driven dosimetry optimization strategy by comparing MTP and single-time-point (STP) dosimetry, and identifying optimal time-points (TPs) for Hänscheid approximation based on therapy outcomes. Methods Clinical and image data from 50 patients were retrospectively analyzed. Transient treatment-emergent adverse events (TEAEs) and prostate-specific antigen (PSA) response were monitored following CTCAE v5.0 and PCWG3. Cycle-level mean absorbed doses ( MTPD tox , and 1d- , 2d- , 3d-STPD tox based on single SPECT acquisitions at 1-, 2-, 3-day(s) p.i.) were computed for organs-at-risk and whole-body tumors. Additionally, cumulative absorbed doses ( STPD cum & MTPD cum ) were derived for whole-body tumors. Results Bone marrow STP dosimetry correlated significantly with anaemia grading ( 1d-STPD tox : Spearman’s ρ=0.35; 2d-STPD tox : Spearman’s ρ=0.41; 3d-STPD tox : Spearman’s ρ=0.46; all p adj <0.001), aligning with MTPD tox (Spearman’s ρ=0.43, p <0.001). Williams’ F -test confirmed no significant difference in correlation strength between STPD tox & MTPD tox derived correlations at any TPs. For PSA response, both MTPD cum (Spearman’s ρ=-0.26, p adj <0.05) and STPD cum ( 1d- & 2d-STPD cum : Spearman’s ρ=-0.34, p adj <0.001) showed significant correlations, without statistically significant differences between STPD cum & MTPD cum derived correlations. Conclusion The outcome-driven TP selection for Hänscheid-based STP dosimetry converges with the physics-based choice within 2-day p.i., the clinically driven approach offers an alternative and complementary strategy for dosimetry development and may facilitate its translation into clinical practice.