“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 isotope 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 a radioactive isotope of iodine attached (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 published in 2008 by Drs Matthay and Dubois provides more information.[5]

References

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 Clin Oncol. 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

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Dr Frank Saran from The Royal Marsden in the UK presented on neuroblastoma during the Paediatric Radiation Oncology Society (PROS) education session Wednesday October 20 at the SIOP meeting in Boston. Prior to his presentation we heard from other specialists on the challenges of using radiation for poor-prognosis brain tumors, particularly high-grade glioma. Other brain tumors discussed were ependymoma, supratentorial primitive neuroectodermal tumors (sPNET), and the emerging use of proton radiation. The difficulty of minimizing neurocognitive damage and the grim prognosis for some of these tumors are very sobering. There was no discussion in this session of treatment for brain metastases for non-CNS tumors. There was also a presentation on radiation for Wilm’s tumor.

Dr Saran gave a short history of studies showing why today radiation is a part of standard therapy for high-risk neuroblastoma (but use of TBI was not discussed). Local failure accounted for a large percentage of relapses when chemo-only regimens were used. In unpublished data supplied by Dr Andrew Pearson,  40% of all stage 4 over 1 year relapsed at the primary site in the ENSG5 study. By contrast in 2001 Memorial-Sloan Kettering (MSKCC) published a series of 99 children with only 10% local failure rate. MSKCC uses hyperfractionated radiation 21 Gy in 14 fractions, usually given in two fractions per day to primary sites and additional radiation to some metastases.  The current SIOP NB trial uses 21 Gy in 14 fractions given over 3 weeks.

Dr Saran also listed current efforts to determine the optimum way to give 131-I MIBG radiation. Some investigations address maintaining oxygenation, fractionating treatment, using radiosensitizers, use of carrier-free (Ultratrace), and adding chemotherapy. A recent European trial showed good results when MIBG radiation therapy was given concurrently with topotecan. Several combination trials (chemo with MIBG) are ongoing in the US and in Europe.

Travel to this meeting was supported by:

• Lighthouse Laboratories

• Max’s Ring of Fire

• Magic Water

• Friends of Will

• Solving Kids’ Cancer

• Children’s Neuroblastoma Cancer Foundation

Pilot study: 131I-MIBG radiotherapy with chemotherapy after induction for newly diagnosed

Dr Greg Yanik (University of Michigan) presented preliminary results of the NANT (New Approaches to Neuroblastoma Therapy) NANT-2001-02 phase 2 MIBG + CEM (131I-MIBG radiotherapy with carboplatin, etoposide, and melphalan) stem cell transplant trial on June 23rd 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden in the “Novel clinical strategies” session. The data are still under review and will be presented at the COG meeting next month. The trial has been completed but the NIH clinical trials listing has not yet been updated to reflect this.[1]

The results of 12 relapsed and refractory children treated in the phase I MIBG+CEM trial was published in 2002.[2]

The encouraging results in the phase II study with 50 refractory children who did not completely respond to induction provide promising expectations for a new pilot trial COG-ANBL09P1 using this concept for frontline therapy for newly diagnosed. The principal investigator is Dr Brian Weiss (Cincinnati Children’s) and the trial will soon begin, accruing 49 patients up to 30 years old in select locations.

Upon completing this protocol, children will also be eligible for the new phase III antibody study using ch14.18 + GM-CSF + IL2 COG-ANBL0931. This trial opened in January 2010 and will accrue 105 (currently open in 29 locations) to further establish safety and efficacy of the antibody ch14.18 given with cytokines GM-CSF and IL2 to obtain FDA approval. This trial is open to all ages.

Is this the first time MIBG will be used in frontline therapy for newly diagnosed (as opposed to just for those refractory at the end of induction)? In 2008 researchers in the Netherlands reported the use of MIBG as initial therapy before chemotherapy and surgery for 44 newly diagnosed high-risk children.

From the abstract:

The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months.

Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%.[3]

References

1. OR58 Phase II trial of MIBG with intensive chemotherapy and Autologous Stem Cell Transplant (ASCT) for high risk neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Study (p. 123 ANR Programme Abstract Book, June 2010)

2. J Clin Oncol. 2002 Apr 15;20(8):2142-9. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. PMID: 11956276

3. 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