Feasibility of high-dose iodine-131-metaiodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and hematopoietic stem cell transplantation: a study protocol

Document Type: Others


1 Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan

2 Department of Nuclear Medicine, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan

3 Innovative Clinical Research Center, Kanazawa University, Japan


Objective(s): High-risk neuroblastoma is a childhood cancer with poor
prognosis despite modern multimodality therapy. Internal radiotherapy using
131I-metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it is
resistant to chemotherapy. The aim of this study is to evaluate the safety and efficacy
of 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapy
and hematopoietic stem cell transplantation.
Methods: Patients with high-risk neuroblastoma will be enrolled in this study. A total
of 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG and
after safety evaluation will undergo high-dose chemotherapy and hematopoietic stem
cell transplantation. Autologous and allogeneic stem cell sources will be accepted.
After engraftment or 28 days after hematopoietic stem cell transplantation, the safety
and response will be evaluated.
Conclusion: This is the first prospective study of 131I-MIBG with high-dose
chemotherapy and hematopoietic stem cell transplantation in Japan. The results will
be the basis of a future nationwide clinical trial.


Main Subjects

  1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369(9579):2106-20.
  2. Pizzo PA, Poplack DG. Principles and practice of pediatric oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
  3. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report. J Clin Oncol. 2009;27(2):289-97.
  4. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33(27):3008-17.
  5. Cotterill SJ, Pearson AD, Pritchard J, Foot AB, Roald B, Kohler JA, et al. Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group “Survey” 1982-1992. Eur J Cancer. 2000;36(7):901-8.
  6. London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group Project. J Clin Oncol. 2011;29(24):3286-92.
  7. Streby KA, Shah N, Ranalli MA, Kunkler A, Cripe TP. Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131 I-mIBG therapy. Pediatr Blood Cancer. 2015;62(1):5-11.
  8. Matthay KK, Desantes K, Hasegawa B, Huberty J, Hattner RS, Ablin A, et al. Phase I dose escalation of 31 1-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol. 1998;16(1):229-36.
  9. Matthay KK, Weiss B, Villablanca JG, Maris JM, Yanik GA, Dubois SG, et al. Dose escalation study of no-carrier-added 131I-metaiodobenzylguanidine for relapsed or refractory neuroblastoma: new approaches to neuroblastoma therapy consortium trial. J Nucl Med. 2012;53(7):1155-63.
10. DuBois SG, Messina J, Maris JM, Huberty J, Glidden DV, Veatch J, et al. Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol. 2004;22(12):2452-60.

11. Yanik GA, Villablanca JG, Maris JM, Weiss B, Groshen S, Marachelian A, et al. 131I-Metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant. 2015;21(4):673-81.

12. Kinuya S, Yoshinaga K, Higuchi T, Jinguji M, Kawamoto H, Kurihara H. Draft guideline regarding appropriate use of 131I-MIBG radiotherapy for neuroendocrine tumors Drafting Committee for Guideline of Radiotherapy with 131I-MIBG, Committee for Nuclear Oncology and Immunology, The Japanese Society of Nuclear Medicine. Kaku Igaku. 2015;52(1):1-15.

13. Giammarile F, Chiti A, Lassmann M, Brans B, Flux G. EANM procedure guidelines for131I-meta-iodobenzylguanidine (131I-mIBG) therapy. Eur J Nucl Med Mol Imaging. 2008;35(5):1039-47.

14. Mazloom A, Louis CU, Nuchtern J, Kim E, Russell H, Allen-Rhoades W, et al. Radiation therapy to the primary and postinduction chemotherapy MIBG-avid sites in high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2014;90(4):858-62.

15. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13- cis -retinoic acid. N Engl J Med. 1999;341(16):1165-73.

16. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013;14(10):999-1008.

17. Ladenstein R, Pötschger U, Pearson AD, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18(4):500-14.

18. Zhou MJ, Doral MY, DuBois SG, Villablanca JG, Yanik GA, Matthay KK. Different outcomes for relapsed versus refractory neuroblastoma after therapy with 131I-metaiodobenzylguanidine (131I-MIBG). Eur J Cancer. 2015;51(16):2465-72.

19. Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, et al. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007;25(9):1054-60.

20. Clement SC, van Rijn RR, van Eck-Smit BL, van Trotsenburg AS, Caron HN, Tytgat GA, et al. Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. Eur J Nucl Med Mol Imaging. 2015;42(5):706-15.

21. Willems L, Waer M, Billiau AD. The graft-versus-neuroblastoma effect of allogeneic hematopoietic stem cell transplantation, a review of clinical and experimental evidence and a perspective on mechanisms. Pediatr Blood Cancer. 2014;61(12):2151-7.

22. Lee JW, Kang ES, Sung KW, Yi E, Lee SH, Yoo KH, et al. Incorporation of high-dose131I-metaiodobenzylguanidine treatment into killer immunoglobulin-like receptor/HLA-ligand mismatched haploidentical stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation. Pediatr Blood Cancer. 2017;64(6):1-8.