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

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.

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.

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.

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.