Double-dose cancer therapy weakens tumor targeting, raising safety questions
A clinical trial of an experimental radioactive treatment for aggressive childhood cancer found that splitting the dose into two sessions reduced tumor uptake by 53% per unit of radiation. The finding challenges the therapeutic logic behind dose-intensified approaches and could reshape how oncologists design treatment protocols for hard-to-treat cancers.
Originaltitel: Fraction-dependent dose dynamics and clinical safety in high-risk neuroblastoma treated with [177Lu]Lu-DOTATATE: results from the LuDO-N trial
**Högre aktivitet i första behandlingsfraktionen optimerar neuroblastomaterapi** Lutetium-177-behandling med DOTATATE visar betydligt bättre tumördoser när aktiviteten ges uppdelat i två fraktioner med högre initial dos. LuDO-N-studien behandlade 14 patienter med högriskneuroblastom enligt ett dosimetriguidat schema: första fraktionen 200 MBq/kg, andra individuellt anpassad två till tre veckor senare. Tumörerna erhöll 53 procent lägre absorberad dos per injicerad aktivitet vid andra fraktionen, medan njur- och helkroppsdoserna minskade med 24 respektive 18 procent. Tumor-till-njur-förhållandet förbättrades med 44 procent mellan fraktionerna. Ingen bestående njurtoxicitet observerades; fyra patienter genomgick stamcellsåterinfusion. Resultaten stödjer en frontlastningsstrategi där högre initialdos maximerar tumörbestrålning. Karolinska Institutet och Princess Máxima Center anpassade därför protokollet till 400 MBq/kg första fraktionen för kommande patienter. Fynd direkt påverkar inköpsbeslut och behandlingsprotokoll inom molekylär radioonkologi.
Abstract Purpose Neuroblastoma frequently overexpresses somatostatin receptors (SSTR), enabling molecular radiotherapy with [ 177 Lu]Lu-DOTATATE ( 177 Lu-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 177 Lu-DOTATATE treatment approach. Methods Fourteen patients with high-risk recurrent or refractory neuroblastoma received 177 Lu-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 177 Lu-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 .