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SIOP 2010 - Therapeutic MIBG for neuroblastoma

"Meet the Experts" session

Drs. Huib Caron (The Netherlands) and Suzanne Shusterman (Boston Childrens/DFCI) presented on MIBG therapy in "Meet the Experts" session Friday Oct 22 and Saturday Oct 23, 2010 at the SIOP meeting in Boston.
Completed and ongoing studies
Dr Caron covered the therapeutic considerations, and Dr. Shusterman spoke about the practical and logistic issues surrounding the design of MIBG therapy rooms and handling the radioactive material.

MIBG (meta-iodobenzylguanidine) is a synthetic analogue to norepinephrine, developed in the 1970s at University of Michigan as a potential agent for use in hypertension. It is taken up by 90% of neuroblastomas. The compound (also called iobenguane) is useful for both imaging with I-123 which has a shorter half-life of 13 hours and produces better resolution images, and radiation therapy with I-131 which has a longer half-life of 8 days.
The compound with radioactive I-131 is taken up in the NB cell but is not lethal to that cell. The beta particles from I-131 decay kills cells up to 2 mm away, and gamma radiation from decay (as in imaging) reaches 2 m or greater distance, but is not lethal to cells in that path. The resulting beta particle decay "cross-fire" is why MIBG radiation therapy appears to be more effective in clumps of disease rather than in diffuse or trace disease. Dr Caron commented in his presentation that this is why he believes using MIBG radiation therapy at the end of induction with minimal or undetectable disease will have questionable efficacy, and why studies in the Netherlands have used double MIBG treatments at the beginning of induction (1989-1999 in 41 children).[1]  Dr Maris countered in a later conversation that there is evidence of efficacy from a double MIBG therapy study where children who respond completely to the first MIBG therapy receive a second MIBG treatment and do well. He also mentioned that it is very common to see much more disease in a post-MIBG therapy scan, revealing that often the imaging dose of MIBG does not show as much disease, and therefore using MIBG therapy at the end of induction even in children with negative MIBG scans may successfully treat undetectable or trace disease. This question (as well as feasibility) will be addressed by the new frontline pilot study now open in several centers using MIBG at the end of induction with CEM transplant for 49 newly diagnosed high-risk NB (see previous article). The German group GPOH is using MIBG therapy in frontline therapy in the ongoing NB2004 study a the end of induction for children who have remaining MIBG positive primary uptake. This study plan is to accrue 360 children.[2]
Other completed and ongoing studies were reviewed, including an ongoing study using MIBG upfront with topotecan in 15 children, a GPOH study using MIBG + gemcitabine phase I/II for refractory and relapsed NB and should finish within the year. The NANT 2007-03 phase I MIBG + vorinostat trial is based on the fact vorinostat (an HDAC inhibitor) increases the norepinephrine transporter expression, and in mice the combination results showed improved response. In 2006 Matthay et al published in JCO the results of the phase I MIBG + CEM transplant in 24 children where the 3-year event-free survival (EFS) was 30% and the 3-year overall survival (OS) was 60% for primary refractory disease. The dose levels from this study were used in the phase II which was recently completed and preliminary results were presented at ANR in June 2010 in Stockholm by Dr Greg Yanik (OR58). MIBG has been tested at 8 to 18 mCi in various trials. In 2007 a Phase II was published in JCO showing promising effectiveness in 164 relapsed or refractory patients with a median of 3 prior regimens (range 1 - 13).[3] A study in the UK planned to use topotecan with MIBG for relapsed or refractory NB closed before it accrued. Another NANT phase I study N2004-06 used MIBG with irinotecan and vincristine, and results are pending. In Sweden a study using haploidentical donor transplant with MIBG was completed in 5 children.[4] In France a study is ongoing using topotecan with MIBG in relapsed and refractory children.
Approval status for 131-I MIBG
131-I MIBG is made by Draximage (a division of Draxis Health) in Canada, and another company Molecular Insights makes Azedra (Ultratrace MIBG with no cold contaminants). 131-I MIBG is approved for treatment of neuroblastoma in Europe, but still an investigational new drug (IND) in the US.
Future focus
Conclusions drawn from this session include the fact that MIBG therapy is obviously an important agent in the treatment of neuroblastoma, with a long history of studies completed since the 1980s. An important challenge for all researchers involved is figuring out the optimum way to use this agent. An excellent review was published in 2008 by Drs. Matthay and Dubois.[5]
1. Eur J Cancer. 2008 Mar;44(4):551-6. Epub 2008 Feb 11. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. PMID: 18267358
2.  Randomized Study of Standard Induction Chemotherapy Versus Topotecan Hydrochloride-Containing Induction Chemotherapy Followed by Myeloablative Autologous Stem Cell Transplantation and Consolidation Therapy With Isotretinoin in Pediatric Patients With High-Risk Neuroblastoma GPOH-NB2004-HR
3. J ClinOncol. 2007 Mar 20;25(9):1054-60. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. PMID: 17369569
4. Biol Blood Marrow Transplant. 2009 Sep;15(9):1077-85. Epub 2009 Jul 8. High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma. PMID: 19660720
5. Q J Nucl Med Mol Imaging. 2008 Dec;52(4):403-18. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. PMID: 19088694
Author: Donna Ludwinski