This study tested the principle that ⁶⁸Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with ¹⁷⁷Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Methods: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with ⁶⁸Ga-DOTATATE PET/CT. The criterion of eligibility for ¹⁷⁷Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Results: Of the 8 children imaged, 6 had abnormally high uptake on the ⁶⁸Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of ¹⁷⁷Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. Conclusion: ⁶⁸Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with ¹⁷⁷Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with ¹⁷⁷Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I–II clinical trial.

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients’ eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2–8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38–47%) and 50% (46–55%) but was 57% (51–62%) and 64% (59–69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Introduction: ¹³¹I-meta iodobenzylguanidine (¹³¹I-mIBG) therapy is established palliation for relapsed neuroblastoma. The topoisomerase-1 inhibitor, topotecan, has direct activity against neuroblastoma and acts as a radiation sensitiser. These 2 treatments are synergistic in laboratory studies. Theoretically, the benefit of ¹³¹I-mIBG treatment could be enhanced by dose escalation and combination with topotecan. Haematological support would be necessary to overcome the myelosuppression, which is the dose-limiting toxicity. Aims: Firstly, one aim of this study was to establish whether in vivo dosimetry could be used to guide the delivery of a precise total whole-body radiation-absorbed dose of 4 Gy accurately from 2 ¹³¹I-mIBG treatments. Secondly, the other aim of this study was to determine whether it is feasible to combine this treatment with the topotecan in children with metastatic neuroblastoma. Material and Methods: An activity of ¹³¹I-mIBG (12 mCi/kg, 444 MBq/kg), estimated to give a whole-body absorbed-radiation dose of approximately 2 Gy, was administered on day 1, with topotecan 0.7 mg/m² administered daily from days 1–5. In vivo dosimetry was used to calculate a 2nd activity of ¹³¹I-mIBG, to be given on day 15 which would give a total whole-body dose of 4 Gy. A further 5 doses of topotecan were given from days 15–19. The myeloablative effect of this regimen was circumvented by peripheral blood stem cell or bone marrow support. Results: Eight children with relapsed stage IV neuroblastoma were treated. The treatment was delivered according to protocol in all patients. There were no unanticipated side-effects. Satisfactory haematological reconstituition occurred in all patients. The measured total whole-body radiation-absorbed dose ranged from 3.7 Gy to 4.7 Gy (mean, 4.2 Gy). Conclusions: In vivo dosimetry allows for a specified total whole-body radiation dose to be delivered accurately. This schedule of intensification of ¹³¹I-mIBG therapy by dose escalation and radiosensitization with topotecan with a haemopoietic autograft is safe and practicable. This approach should now be tested for efficacy in a phase II clinical trial.

The aim of our study was to evaluate prospectively the diagnostic performance and prognostic significance of ¹⁸F-FDG PET/CT in comparison with ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) imaging in patients with high-risk neuroblastoma. Methods: Twenty-eight patients with refractory or relapsed high-risk neuroblastoma (16 male and 12 female patients; age range, 2–45 y; median age, 7.5 y) were simultaneously evaluated with ¹⁸F-FDG PET/CT and ¹²³I-MIBG imaging before treatment with high-dose ¹³¹I-MIBG. We compared the 2 methods in mapping tumor load, according to the extent of disease and intensity of positive lesions identified in each patient. Separate comparisons were performed for the soft-tissue and bone–bone marrow components of tumor burden. Survival analysis was performed to assess the prognostic significance of ¹⁸F-FDG and ¹²³I-MIBG imaging parameters. Results: ¹⁸F-FDG PET/CT results were positive in 24 of 28 (86%) patients, whereas ¹²³I-MIBG imaging results were positive in all patients. ¹⁸F-FDG was superior in mapping tumor load in 4 of 28 (14%) patients, whereas ¹²³I-MIBG was better in 12 of 28 (43%) patients. In the remaining 12 (43%) patients, no major differences were noted between the 2 modalities. ¹⁸F-FDG PET/CT missed 5 cases of bone–bone marrow disease, 4 cases of soft-tissue disease, and 6 cases of skull involvement that were positive on ¹²³I-MIBG scans. Cox regression and Kaplan–Meier survival curves showed that the group of patients (4/28) in whom ¹⁸F-FDG was superior to ¹²³I-MIBG had a significantly lower survival rate than the others. Tumoral avidity for ¹⁸F-FDG (maximum standardized uptake value) and extent of ¹⁸F-FDG–avid bone–bone marrow disease were identified as adverse prognostic factors. Conclusion: ¹²³I-MIBG imaging is superior to ¹⁸F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, ¹⁸F-FDG PET/CT has significant prognostic implications in these patients.