What is the role of MIBG (Metaiodobenzylguanidine) therapy in the treatment of newly diagnosed high-risk neuroblastoma?

Role of MIBG Therapy in Newly Diagnosed High-Risk Neuroblastoma

MIBG therapy is NOT currently recommended as standard frontline treatment for newly diagnosed high-risk neuroblastoma, but is being actively investigated in clinical trials and may be considered in select cases based on emerging evidence. The NCCN 2024 guidelines do not include therapeutic 131I-MIBG as part of standard induction, consolidation, or post-consolidation therapy for newly diagnosed patients 1.

Current Standard of Care

The established treatment paradigm for newly diagnosed high-risk neuroblastoma consists of 2, 3:

• Induction chemotherapy: 5-cycle ANBL12P1 or ANBL1531 protocols (topotecan, cyclophosphamide, cisplatin, etoposide, doxorubicin)
• Surgical resection of primary tumor
• Consolidation: Tandem autologous stem cell transplantation with high-dose chemotherapy
• Post-consolidation immunotherapy: Anti-GD2 antibody (dinutuximab) with sargramostim and isotretinoin 4
• Continuation therapy: Eflornithine for patients achieving partial response or better 1

Notably absent from this algorithm is therapeutic 131I-MIBG 1.

Diagnostic vs. Therapeutic Use of MIBG

It is critical to distinguish between diagnostic and therapeutic applications of MIBG:

Diagnostic MIBG (123I-MIBG) - Standard Practice

• 123I-MIBG scanning is the cornerstone imaging modality for staging and response assessment in neuroblastoma 1
• Full disease evaluation includes 123I-MIBG scan at end of induction, start of post-consolidation, and end of therapy 1
• MIBG is more sensitive and specific than technetium-99m bone scintigraphy 1
• Patients with >5 residual MIBG-avid sites after induction should have repeat scanning after stem cell rescue to prioritize metastatic sites for consolidative radiotherapy 1

Therapeutic MIBG (131I-MIBG) - Investigational in Frontline Setting

• Not included in current NCCN standard treatment algorithms for newly diagnosed patients 1
• Primarily used in relapsed/refractory disease with 30-40% response rates 5, 6

Emerging Evidence for Upfront 131I-MIBG Therapy

Despite not being standard, several studies suggest potential benefit of incorporating 131I-MIBG into frontline therapy:

Children's Oncology Group Pilot Study (2021)

A COG feasibility trial (NCT01175356) demonstrated 7:

• Feasibility rate of 96.7% at 15 mCi/kg dose level when administered after induction chemotherapy
• 86.8% of patients who completed induction received 131I-MIBG
• Major toxicity concern: Sinusoidal obstruction syndrome (SOS) occurred in 23.5-33.3% at various dose levels
• Required 10-week gap before busulfan/melphalan consolidation to mitigate SOS risk
• This laid groundwork for randomized trial NCT03126916 testing addition of 131I-MIBG during induction

European Experience (2017)

A Dutch multi-center pilot study showed 8:

• 38% response rate after upfront 131I-MIBG (before chemotherapy)
• 71% response rate post-consolidation in MIBG-treated patients vs. 36% in chemotherapy-only group
• Treatment was feasible within 2 weeks of diagnosis in 95% of eligible patients
• Delayed platelet recovery post-transplant in MIBG-treated patients
• No stem cell support needed after 131I-MIBG therapy itself

Italian Single-Center Experience (2023)

Retrospective data combining 131I-MIBG with intensive chemotherapy at diagnosis showed 9:

• 87% objective response rate when 131I-MIBG (up to 18.3 mCi/kg) was given on day 10 with 5-drug chemotherapy combination
• Acceptable hematological toxicity
• Authors advocate for inclusion in all induction regimens, though this represents single-center experience

Critical Limitations of Current Evidence

The evidence base has significant weaknesses 5:

• No randomized controlled trials comparing treatment with vs. without upfront 131I-MIBG in newly diagnosed patients
• Only small observational studies and single-arm trials available
• High risk of bias in existing studies
• Cochrane review (2017) concluded: "We cannot make recommendations for the use of 131I-MIBG therapy in patients with newly diagnosed HR NBL in clinical practice" 5
• Significant toxicity concerns, particularly SOS when combined with alkylating agents 7

When to Consider 131I-MIBG in Newly Diagnosed Patients

In clinical practice, therapeutic 131I-MIBG for newly diagnosed high-risk neuroblastoma should only be considered in these specific scenarios:

1. Clinical trial enrollment - Patients should be offered participation in ongoing randomized trials (e.g., NCT03126916) 7

2. Inadequate response to standard induction - For patients with persistent disease after standard chemotherapy, 131I-MIBG may be considered as part of salvage strategy before consolidation, though this transitions toward refractory disease management 2

3. MIBG-avid disease only - Approximately 10% of neuroblastomas are MIBG non-avid, making this therapy inappropriate 1, 8

Critical Pitfalls to Avoid

• Do not delay standard therapy to pursue 131I-MIBG outside of clinical trials - the established multimodal approach has proven survival benefit 2, 3

• Do not confuse diagnostic with therapeutic MIBG - diagnostic 123I-MIBG scanning is essential and standard; therapeutic 131I-MIBG is investigational in frontline setting 1

• Beware of sinusoidal obstruction syndrome - if 131I-MIBG is used, adequate time interval (≥10 weeks) before myeloablative therapy with busulfan is critical 7

• Ensure adequate thyroid blockade - required for all MIBG administration 1

• Monitor for delayed platelet recovery - may be prolonged after subsequent stem cell transplantation 8

Practical Algorithm for Decision-Making

For a newly diagnosed high-risk neuroblastoma patient:

1. Confirm MIBG-avidity with diagnostic 123I-MIBG scan (required for staging regardless) 1

2. Assess clinical trial availability - prioritize enrollment in randomized trials testing upfront 131I-MIBG 7

3. If no trial available: Proceed with standard NCCN-recommended induction chemotherapy (ANBL12P1 or ANBL1531) 2, 3

4. Reassess after induction 2:

   • Adequate response → proceed to consolidation per standard protocol
   • Inadequate response → consider 131I-MIBG as part of salvage approach with multidisciplinary discussion
   • Progressive disease → transition to non-myeloablative approaches

5. Reserve therapeutic 131I-MIBG primarily for relapsed/refractory disease where it has established efficacy 5, 6

Future Directions

The ongoing COG randomized trial (NCT03126916) will provide definitive evidence regarding the role of 131I-MIBG in newly diagnosed high-risk neuroblastoma 7. Until these results are available, therapeutic 131I-MIBG remains investigational in the frontline setting, and standard multimodal therapy without 131I-MIBG should be the default approach 1.