Dose escalation study of no-carrier-added 131I-metaiodobenzylguanidine for relapsed or refractory neuroblastoma: new approaches to neuroblastoma therapy consortium trial.
(131)I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%-37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of (131)I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) (131)I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response.


METHODS
Eligible patients were 1-30 y old with resistant neuroblastoma, (131)I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA (131)I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA (131)I-MIBG (specific activity, 165 MBq/μg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA (131)I-MIBG was escalated from 444 to 777 MBq/kg (12-21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/μL within 28 d or platelets to greater than 20,000/μL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions.


RESULTS
Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease.


CONCLUSIONS
NCA (131)I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.
Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA. matthayk@peds.ucsf.edu
Katherine K
KK
Matthay
Brian
B
Weiss
Judith G
JG
Villablanca
John M
JM
Maris
Gregory A
GA
Yanik
Steven G
SG
Dubois
James
J
Stubbs
Susan
S
Groshen
Denice
D
Tsao-Wei
Randall
R
Hawkins
Hollie
H
Jackson
Fariba
F
Goodarzian
Heike
H
Daldrup-Link
Ashok
A
Panigrahy
Alexander
A
Towbin
Hiroyuki
H
Shimada
John
J
Barrett
Norman
N
Lafrance
John
J
Babich
D019797:3-Iodobenzylguanidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000532:radiotherapy*; D002626:Chemistry, Pharmaceutical; D002648:Child; D002675:Child, Preschool; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000532:radiotherapy; D009447:Neuroblastoma / Q000532:radiotherapy*; D011788:Quality of Life; D011829:Radiation Dosage; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D012984:Software; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D055815:Young Adult
D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine