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

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 [177Lu]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 (MTPDtox, and 1d-, 2d-, 3d-STPDtox 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 (STPDcum & MTPDcum) were derived for whole-body tumors.Results Bone marrow STP dosimetry correlated significantly with anaemia grading (1d-STPDtox: Spearman's ρ=0.35;2d-STPDtox: Spearman's ρ=0.41; 3d-STPDtox: Spearman's ρ=0.46; all padj<0.001), aligning with MTPDtox (Spearman's ρ=0.43, p<0.001). Williams' F-test confirmed no significant difference in correlation strength between STPDtox & MTPDtox derived correlations at any TPs. For PSA response, both MTPDcum (Spearman's ρ=-0.26, padj<0.05) and STPDcum (1d-&2d-STPDcum: Spearman's ρ=-0.34, padj<0.001) showed significant correlations, without statistically significant differences between STPDcum & MTPDcum 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.