Fraction-dependent dose dynamics and clinical safety in high-risk neuroblastoma treated with [¹⁷⁷Lu]Lu-DOTATATE: results from the LuDO-N trial

Purpose: Neuroblastoma frequently overexpresses somatostatin receptors (SSTR), enabling molecular radiotherapy with [¹⁷⁷Lu]Lu-DOTATATE (¹⁷⁷Lu-DOTATATE). Based on prior studies suggesting that dose intensification is required to achieve objective responses, the LuDO-N trial employs a two-fraction, high-activity treatment regimen. This study aimed to evaluate fraction-dependent changes in tumour and risk-organ absorbed doses, as well as the clinical safety of the intensified ¹⁷⁷Lu-DOTATATE treatment approach. Methods: Fourteen patients with high-risk recurrent or refractory neuroblastoma received ¹⁷⁷Lu-DOTATATE in a dose-intensified, dosimetry-guided regimen. Treatment was given in two fractions 2–3 weeks apart, targeting a cumulative dose of either 2.4 Gy to the whole body or 23 Gy to either kidney. The first fraction was administered at 200 MBq/kg, while the second fraction was individually adjusted to achieve the dosimetric targets. Results: Tumour-to-kidney and tumour-to-whole-body absorbed dose ratios both decreased significantly by 44% after the second fraction, compared to the first. Tumours received a median 53% lower absorbed dose per administered activity in the second fraction, while kidney and whole-body doses per activity were reduced by 24% and 18%, respectively. Four of fourteen patients (29%) underwent peripheral blood stem cell reinfusion. No sustained renal toxicity was observed. Conclusions: These findings support a front-loaded ¹⁷⁷Lu-DOTATATE strategy to maximise tumour irradiation while maintaining exposure to risk organs within safety limits. Accordingly, the LuDO-N protocol has been amended to increase administered activity to 400 MBq/kg in the first fraction for subsequent patients. Together, this work contributes to the ongoing optimisation of dosimetry-guided and intensified treatment strategies for SSTR-targeted molecular radiotherapy for high-risk neuroblastoma. Clinical trial registration: EU Clinical Trials Register, EU CT 2023-503684-42-00. Registered 2021-05-21. https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2023-503684-42-00.