Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma

Department of Pediatrics, University of California at San Francisco, and UCSF Children's Hospital, San Francisco, CA 94143-0106, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 04/2007; 25(9):1054-60. DOI: 10.1200/JCO.2006.09.3484
Source: PubMed


To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma.
One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG. Those without hematopoietic stem cells (n = 16) received 12 mCi/kg. Patients were stratified according to prior myeloablative therapy and whether they had measurable soft tissue involvement or only bone and/or bone marrow disease.
Hematologic toxicity was common, with 33% of patients receiving autologous hematopoietic stem cell support. Nonhematologic grade 3 or 4 toxicity was rare, with 5% of patients experiencing hepatic, 3.6% pulmonary, 10.9% infectious toxicity, and 9.7% with febrile neutropenia. The overall complete plus partial response rate was 36%. The response rate was significantly higher for patients with disease limited either to bone and bone marrow, or to soft tissue (compared with patients with both) for patients with fewer than three prior treatment regimens and for patients older than 12 years. The event-free survival (EFS) and overall survival (OS) times were significantly longer for patients achieving response, for those older than 12 years and with fewer than three prior treatment regimens. The OS was 49% at 1 year and 29% at 2 years; EFS was 18% at 1 year.
The high response rate and low nonhematologic toxicity with 131I-MIBG suggest incorporation of this agent into initial multimodal therapy of neuroblastoma.

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    • "Unfavorable NBs are also classified as high-risk NB and are characterized by widespread tumor dissemination, late relapse and poor long-term survival. Among the current treatments for high-risk NB, 131I-metaiodobenzylguanidine (MIBG) has been used for scintigraphic detection and the targeted radiotherapy of NB (1,2). The use of 131I-MIBG in clinical practice for the treatment of patients with NB is based on the fact that MIBG is a norepinephrine analogue and that NBs often express norepinephrine transporters or NET. "
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    ABSTRACT: In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects.
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    • "Infections have also been reported during and after 131I-MIBG therapy in heavily pretreated patients and in patients treated with myeloablative 131I-MIBG therapy [8]. Matthay et al. found infectious events (grade 3 or 4) in 10.9 % of patients with refractory neuroblastoma [9]. In contrast, only a few patients in our cohort were diagnosed with infections not exceeding grade II in severity. "
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    ABSTRACT: In the treatment of patients with high-risk neuroblastoma, different doses of (131)I-metaiodobenzylguanidine ((131)I-MIBG) are administered at different time points during treatment. Toxicity, mainly haematological (thrombocytopenia), from (131)I-MIBG therapy is known to occur in extensively chemotherapy pretreated neuroblastoma patients. Up to now, acute toxicity from (131)I-MIBG as initial treatment has never been studied in a large cohort. The aim of this retrospective study was to document acute toxicity related to upfront (131)I-MIBG. All neuroblastoma patients (stages 1-4 and 4S) treated upfront with (131)I-MIBG at the Emma Children's Hospital, Academic Medical Centre (1992 - 2008) were included in this retrospective analysis. The acute toxicity (during therapy) and short-term toxicity (1st month following therapy) of the first two (131)I-MIBG therapies were studied. Of 66 patients (34 boys, 32 girls; median age 2.2 years, range 0.1 - 9.4 years), 49 had stage 4 disease, 5 stage 4S, 6 stage 3, 1 stage 2 and 5 stage 1. The median first dose was 441 MBq/kg (range 157 - 804 MBq/kg). The median second dose was 328 MBq/kg (range 113 - 727 MBq/kg). The most frequently observed symptoms were nausea and vomiting (21 %, maximum grade II). The main toxicity was grade IV haematological, occurring only in stage 4 patients, after the first and second (131)I-MIBG therapies: anaemia (5 % and 4 %, respectively), leucocytopenia (3 % and 4 %) and thrombocytopenia (2 % and 4 %). No stem cell rescue was needed. The main acute toxicity observed was haematological followed by nausea and vomiting. One patient developed posterior reversible encephalopathy syndrome during (131)I-MIBG therapy, possibly related to (131)I-MIBG. We consider (131)I-MIBG therapy to be a safe treatment modality.
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    • "Since NB frequently has heterogeneous neoplastic populations which are highly variable in their state of differentiation, it has been predicted that failure of the neural crest cells to fully differentiate causes the development of neuroblastoma [1]. These have been extensively studied as a neoplastic model and to develop differentiation based chemo-therapies [1], [2] that are often complicated by the requirement of high doses and their cytotoxicity. Amongst others, retinoid-based differentiation and maintenance therapy has relatively increased survival rate for NB patients, however, there is still a significantly considerable number of patients showing relapse and deteriorated phases of NB [3], [4], [5]. "
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