Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma.

OBJECTIVE: Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach. MATERIALS AND METHODS: A review of 44 treatments in 25 patients treated with I-mIBG therapy was performed. Patients received I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients. RESULTS: The mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease. CONCLUSION: A highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-mIBG therapy.

Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma.

UNLABELLED: The aims of this study were to examine the relationship between whole-body absorbed dose and hematologic toxicity and to assess the most accurate method of delivering a prescribed whole-body absorbed dose in (131)I-metaiodobenzylguanidine ((131)I-MIBG) therapy for neuroblastoma. METHODS: A total of 20 children (1-12 y), 5 adolescents (13-17 y), and 1 adult (20 y) with stage 3 or 4 neuroblastoma were treated to a prescribed whole-body absorbed dose, which in most cases was 2 Gy. Forty-eight administrations of (131)I-MIBG were given to the 26 patients, ranging in activity from 1,759 to 32,871 MBq. For 30 administrations, sufficient data were available to assess the effect of whole-body absorbed dose on hematologic toxicity. Comparisons were made between the accuracy with which a whole-body absorbed dose could be predicted using a pretherapy tracer study and the patient's most recent previous therapy. The whole-body absorbed dose that would have been delivered if the administered activity was fixed (7,400 MBq) or determined using a weight-based formula (444 MBq.kg(-1)) was also estimated. RESULTS: The mean whole-body absorbed dose for patients with grade 4 Common Terminology Criteria for Adverse Events (CTCAE) neutropenia after therapy was significantly higher than for those with grade 1 CTCAE neutropenia (1.63 vs. 0.90 Gy; P = 0.05). There was no correlation between administered activity and hematologic toxicity. Absorbed whole-body doses predicted from previous therapies were within +/-10% for 70% of the cases. Fixed-activity administrations gave the largest range in whole-body absorbed dose (0.30-3.11 Gy). CONCLUSION: The results indicate that even in a highly heterogeneous and heavily pretreated patient population, a whole-body absorbed dose can be prescribed accurately and is a more accurate predictor of hematologic toxicity than is administered activity. Therefore, a whole-body absorbed dose can be used to deliver accurate and reproducible (131)I-MIBG therapy on a patient-specific basis.

Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma.

INTRODUCTION: (131)I-meta iodobenzylguanidine ((131)I-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 (131)I-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 (131)I-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 (131)I-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/m(2) administered daily from days 1-5. In vivo dosimetry was used to calculate a 2nd activity of (131)I-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 reconstitution 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 (131)I-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.

Absorbed dose ratios for repeated therapy of neuroblastoma with I-131 mIBG.

Patients undergoing targeted radionuclide therapy (TRT) may receive a series of two or more treatment administrations at varying intervals. However, the level of activity administered and the frequency of administration can vary widely from centre to centre for the same therapy. Tumour dosimetry is seldom employed to determine the optimum treatment plan mainly due to the potential inaccuracies of image quantification. In this work 3D dose distributions obtained from repeated therapies have been registered to enable the dose ratios to be determined. These ratios are independent of errors in image quantification and, since the same target volume can be transferred from one distribution to the next, independent of inconsistencies in outlining these volumes. These techniques have initially been applied to ten sets of I-131 mIBG therapy scan data from five patients, each undergoing two therapies. It was found that where a similar level of activity was administered for the second therapy, a similar tumour dose was delivered, and in two cases where a higher level of activity was administered for the second treatment, a correspondingly higher absorbed dose was delivered. This justifies an approach of administering activities based on individual patient kinetics rather than administering standard activities to all patients.