Feasibility of Dosimetry-Based High-Dose 131I-Meta-Iodobenzylguanidine with Topotecan as a Radiosensitizer in Children with Metastatic Neuroblastoma

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Abstract
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.