Long-term toxicity of tandem radioligand therapy using [

purposeRadioligand therapy (RLT) targeting somatostatin receptors is an established treatment for advanced neuroendocrine tumors (NETs). While long-term safety data for [¹⁷⁷Lu]Lu-DOTA-TATE monotherapy are increasingly available, evidence regarding late toxicity of tandem RLT combining ⁹⁰Y- and ¹⁷⁷Lu-labeled somatostatin analogues remains limited. We evaluated the long-term safety profile of tandem [⁹⁰Y]Y/[¹⁷⁷Lu]Lu-DOTA-TATE RLT in a large real-world cohort with extended follow-up.

methodsThis retrospective study included 89 patients with NETs treated between 2002 and 2016 and followed for 9-20 years. Long-term renal, hematological, and hepatic toxicities were assessed. Renal function was analyzed longitudinally using patient-level annual estimated eGFR decline and time-to-event analysis for chronic kidney disease (CKD). Patients undergoing repeated RLT were analyzed separately.

resultsGrade ≥ 3 nephrotoxicity was observed in 3.4%. Median annual eGFR decline was - 2.1 mL/min/1.73 m² and was significantly steeper in patients with nephrotoxicity (- 4.2 vs. -1.6 mL/min/1.73 m²/year; p < 0.001). The cumulative incidence of CKD reached 51% at 10 years, while no cases of end-stage renal disease requiring dialysis or transplantation were observed. Grade ≥ 3 thrombocytopenia occurred in 5.6%, and one case of myelodysplastic syndrome was observed after supra-standard cumulative activity. Among patients undergoing repeated tandem RLT (16.9%), no statistically significant excess long-term renal or hematological toxicity was detected.

conclusionTandem RLT was associated with low rates of severe late toxicity, even after very prolonged follow-up and repeated treatment courses, although gradual long-term decline in renal function was common. These data provide a rare long-term real-world benchmark for late toxicity of high-energy β-emitter-based RLT and support the long-term feasibility of tandem RLT in selected patients with NETs.