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

Purpose To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine (I-131-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. I-131-MIBG was administered on day -21, CEM was acid. 131 I-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 m(2)) was I-131-MIBG 12 mCi/kg, carboplatin 1,500 mg/m(2), etoposide 1,200 mg/m(2), and melphalan 210 mg/m(2). In the low-GFR cohort, at the initial dose level using 12 mCi/kg of I-131-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOID). 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/mu L of 10 days and median time for platelets >= 20,000/mu L 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 I-131-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.