Dosimetry-Guided Radioligand Therapy in Neuroendocrine Tumors: Interim Safety Analysis of the DUONEN Trial

Maciej Kolodziej¹Marta Opalinska^2*Renata Mikolajczak³Alicja Hubalewska-Dydejczyk²Marek Dedecjus⁴Aldona Kowalska⁵Marek Saracyn⁶Piotr Garnuszek³Izabela Cieszykowska³Joanna Januszkieicz-Caulier⁴Joanna Dlugosinska⁴Adam Durma⁶Katarzyna Jozwik-Plebanek⁶Adrianna Mróz⁶Katarzyna Janiak⁶Danuta Gasior-Perczak⁵Malgorzata Trofimiuk-Muldner²Anna Sowa-Staszczak²Janusz Braziewicz⁷Wioletta Lenda-Tracz⁸Krzysztof Kacperski⁹Anna Budzynska⁹Agata Kubik⁹Patrycja Pastusiak⁹Wioletta Chalewska⁴Anna Borkowska¹⁰Paulina Cegla⁴Agata Walecka-Mazur¹¹Artur Szczodry¹¹Grzegorz Wiktor Kaminski⁴

• ¹Department of Endocrinology and Isotope Therapy, Military Institute of Medicine - National Research Institute,, Warsaw, Poland
• ²Chair and Department of Endocrinology, Jagiellonian University Medical College, Krakow, Poland
• ³Radioisotope Centre POLATOM, National Centre for Nuclear Research, Otwock, Poland
• ⁴Department of Endocrine Oncology and Nuclear Medicine, National Institute of Oncology - National Research Institute, Warsaw, Poland
• ⁵Collegium Medicum, Jan Kochanowski University, Kielce, Poland
• ⁶Department of Endocrinology and Isotope Therapy, Military Institute of Medicine - National Research Institute, Warsaw, Poland
• ⁷Department of Nuclear Medicine, Holy Cross Cancer Center, Kielce, Poland
• ⁸Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
• ⁹Department of Nuclear Medicine, Military Institute of Medicine - National Research Institute, Warsaw, Poland
• ¹⁰Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland, Krakow, Poland
• ¹¹Department of Endocrinology, Holy Cross Cancer Center, Kielce, Poland

Background: PRRT with [¹⁷⁷Lu]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 ⁹⁰Y/¹⁷⁷Lu 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 [¹⁷⁷Lu]Lu-DOTA-TATE (arm A) with three dosimetry-guided regimens: arm B (¹⁷⁷Lu+⁹⁰Y, variable ⁹⁰Y); arm C (¹⁷⁷Lu+⁹⁰Y, variable ¹⁷⁷Lu); arm D (variable ¹⁷⁷Lu). 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 ⁹⁰Y 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 ¹⁷⁷Lu escalation and tandem ⁹⁰Y/¹⁷⁷Lu. DUONEN provides the first randomized prospective evidence for isotope-and patient-tailored PRRT dosing. Long-term follow-up will clarify their impact on efficacy. Acknowledgment: The study was funded by the Medical Research Agency, Poland (project number 2019/ABM/01/00077). The study was registered in EudraCT 2020-006068-99 (September 20, 2021).