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


METHODS
Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-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. (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 (> or = 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 > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL 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.


CONCLUSIONS
131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.
Matthay
Katherine K
KK
Department of Pediatrics, University of California, San Francisco, School of Medicine, and UCSF Children's Hospital, San Francisco, CA 94143-0106, USA. matthayk@peds.ucsf.edu
Tan
Jessica C
JC
Villablanca
Judith G
JG
Yanik
Gregory A
GA
Veatch
Janet
J
Franc
Benjamin
B
Twomey
Eilish
E
Horn
Biljana
B
Reynolds
C Patrick
CP
Groshen
Susan
S
Seeger
Robert C
RC
Maris
John M
JM
D019797:3-Iodobenzylguanidine / Q000008:administration & dosage* / Q000009:adverse effects*; D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D009447:Neuroblastoma / Q000188:drug therapy* / Q000601:surgery*; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019797:3-Iodobenzylguanidine; D005047:Etoposide; D016190:Carboplatin; D008558:Melphalan