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Phase I Dose Escalation of Iodine-131–Metaiodobenzylguanidine With Myeloablative Chemotherapy and Autologous Stem-Cell Transplantation in Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study

From the Department of Pediatrics and Radiology, University of California, San Francisco (UCSF), School of Medicine, and UCSF Children's Hospital, San Francisco; Department of Pediatrics and Preventive Medicine, Keck School of Medicine, University of Southern California and Children's Hospital Los Angeles, Los Angeles, CA; Department of Pediatrics, University of Michigan and Mott Children's Hospital, Ann Arbor, MI; and the Department of Pediatrics, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA.

Address reprint requests to Katherine K. Matthay, MD, Department of Pediatrics, University of California, San Francisco, 505 Parnassus, M647, San Francisco, CA 94143-0106; e-mail: matthayk{at}peds.ucsf.edu

Purpose To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131–metaiodobenzylguanidine (¹³¹I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.

Patients and Methods Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. ¹³¹I-MIBG was administered on day –21, CEM was administered on days –7 to –4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. ¹³¹I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).

Results The MTD for patients with normal GFR ( 100 mL/min/1.73 m²) was ¹³¹I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m², etoposide 1,200 mg/m², and melphalan 210 mg/m². In the low-GFR cohort, at the initial dose level using 12 mCi/kg of ¹³¹I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils 500/µL of 10 days and median time for platelets 20,000/µL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 ± 0.10 and 0.58 ± 0.10, respectively.

Conclusion ¹³¹I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

Supported by the National Institutes of Health Grants No. PO1 CA81403, 2MO1 RR0127, and M01-RR00240, as well by donations from the Campini Foundation, the Conner Research Fund, the Katie Dougherty Foundation, Kasle and Tkalcevik Neuroblastoma Research Fund, Alex's Lemonade Stand, the Pediatric Cancer Research Fund, the Evan Dunbar Foundation, the Milkin Family Foundation, and the Philadelphia Foundation.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 14-16, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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