Dosimetry-guided peptide receptor radionuclide therapy in neuroendocrine tumors: interim safety analysis of the DUONEN trial

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Abstract
Background: PRRT with [ 177 Lu]Lu-DOTA-TATE improves survival in advanced GEP-NETs, but fixed-activity dosing may result in undertreatment or unnecessary toxicity. Individualized dosimetry and tandem-PRRT with 90 Y/ 177 Lu have been proposed, but prospective randomized evidence is lacking. Methods: DUONEN is an ongoing multicenter, randomized phase 3 trial (N = 92 planned; 56 analyzed) comparing standard fixed-activity [ 177 Lu]Lu-DOTA-TATE (arm A) with three dosimetry-guided regimens: arm B ( 177 Lu+ 90 Y, variable 90 Y); arm C ( 177 Lu+ 90 Y, variable 177 Lu); arm D (variable 177 Lu). Organ dosimetry was performed after each cycle, with per-cycle activity modifications to respect kidney (23 Gy) and marrow (2 Gy) thresholds. Safety was assessed by laboratory, renal, and hepatic parameters. Results: Activity reductions predominated in arms B and C, while increases were common in arm D. Median cumulative kidney and marrow doses were highest in arm C (29.1 Gy and 0.79 Gy, respectively), driven by 90 Y contribution. Hematologic declines were observed across all arms, most prominently in lymphocytes and platelets, and correlated with marrow dose but not with categorical dose modifications. Renal function remained stable, and no clinically relevant hepatotoxicity occurred. Conclusions: This interim analysis demonstrates the feasibility and safety of dosimetry-guided PRRT strategies, including individualized 177 Lu escalation and tandem 90 Y/ 177 Lu. DUONEN provides the first randomized prospective evidence for isotope- and patient-tailored PRRT dosing. Long-term follow-up will clarify their impact on efficacy. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-006068-99 , identifier 2020-006068-99.

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