What are the stage-wise recommended management strategies for neuroblastoma, including chemotherapy (chemo) regimens, radiation doses and volumes, and Autologous Stem Cell Transplantation (ASCT)/anti-GD2 targeted therapy, according to the Children's Oncology Group (COG) guidelines?

Stage-Wise Management of Neuroblastoma per COG Guidelines

Low-Risk Neuroblastoma

For low-risk INRG L1 tumors, surgical resection is the primary treatment, with observation alone appropriate for infants <6 months with isolated adrenal masses ≤3.1 cm if solid or ≤5 cm if ≥25% cystic. 1

Treatment Approach:

• Surgery alone is the standard approach when resection can be performed safely with minimal morbidity 1
• Observation without biopsy is recommended for select neonates with small adrenal masses meeting size criteria 1
• For asymptomatic INRG MS disease with favorable biology, observation is the preferred approach 1
• If incomplete resection reveals MYCN amplification, immediately reassign to high-risk group 1
• No chemotherapy or radiation is required for most low-risk patients 1
• 5-year survival exceeds 95% with this minimal intervention approach 1

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Intermediate-Risk Neuroblastoma

Intermediate-risk patients require 2-8 cycles of chemotherapy based on age, stage, and biologic features, with the goal of achieving 50-90% tumor volume reduction before considering surgical resection. 1

Chemotherapy Regimen:

• Cyclophosphamide-based regimens are standard (specific agents from ANBL0531 protocol) 1
• Number of cycles determined by:
  • Disease stage (L2 vs M vs MS)
  • Age at diagnosis
  • Biologic features (histology, DNA index, segmental chromosomal aberrations) 1

Response Goals:

• Localized favorable biology tumors: Achieve ≥50% reduction in primary tumor volume 1
• Localized unfavorable biology tumors: Continue therapy until 90% reduction in primary tumor volume 1
• Response assessment uses either volume measurements or single-dimension RECIST criteria 1

Surgical Approach:

• Timing: After achieving target tumor reduction with chemotherapy 1
• Extent: Preservation of vital structures and end-organ function is paramount; less than complete resection is acceptable 1
• Consider surgery if chemotherapy results in <50% tumor size reduction 1
• If surgery cannot be performed safely, give additional chemotherapy with re-evaluation every 2 cycles 1

Radiation:

• Not routinely indicated for intermediate-risk disease 1

Expected Outcomes:

• 5-year survival: 90-95% 1

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High-Risk Neuroblastoma

High-risk neuroblastoma requires intensive multimodality therapy consisting of induction chemotherapy (5 cycles ANBL12P1/ANBL1531), surgical resection, consolidation with tandem autologous stem cell transplantation, radiation therapy, and immunotherapy with anti-GD2 antibody plus 13-cis-retinoic acid. 2, 3

Phase 1: Induction Chemotherapy

Regimen: 5 cycles of ANBL12P1 or ANBL1531 protocol 2

Specific agents include: 2

• Cycles 1-2: Topotecan + Cyclophosphamide
• Subsequent cycles: Cisplatin + Etoposide and Doxorubicin-based combinations
• Response rate: ~80% achieve partial response or better 2

During induction: 2

• Collect autologous peripheral blood stem cells for later transplantation
• Perform surgical resection of primary tumor and locoregional disease when feasible
• Goal: ≥90% resection of primary tumor is both feasible and safe in most patients 4

Phase 2: Consolidation with Tandem ASCT

Tandem transplantation with two consecutive rounds of high-dose chemotherapy is the standard consolidation approach, demonstrating superior 3-year event-free survival (61.6% vs 48.4%) compared to single transplant. 2

First transplant regimen: 2

• Thiotepa + Cyclophosphamide

Second transplant regimen: 2

• Reduced-dose Carboplatin + Etoposide + Melphalan (CEM)

Alternative European regimen: 2

• Busulfan + Melphalan (BuMel) shows superior EFS but higher risk of sinusoidal obstruction syndrome

Exceptions to tandem transplant (single transplant may be appropriate): 2

• Stage L2, ≥18 months, unfavorable histology, MYCN non-amplified
• Stage M, 12 to <18 months, MYCN non-amplified with unfavorable histology, diploid DNA, or segmental chromosomal aberrations

Patients NOT eligible for consolidation: 2

• Progressive disease during induction → proceed to non-myeloablative therapies
• Minor response or stable disease → requires individualized assessment

Phase 3: Radiation Therapy

Radiation is administered to residual soft tissue disease sites after consolidation. 3

Timing: After autologous stem cell transplant, before immunotherapy 3

Volumes: Target residual primary tumor bed and metastatic sites with measurable disease 3

Dose: Specific doses not detailed in provided guidelines but administered to residual disease sites 3

Phase 4: Immunotherapy (Anti-GD2 Targeted Therapy)

Dinutuximab (anti-GD2 monoclonal antibody) combined with GM-CSF, IL-2, and 13-cis-retinoic acid is administered for up to 5 cycles, followed by 1 cycle of retinoic acid alone. 3

Dinutuximab dosing: 3

• 17.5 mg/m²/day as diluted intravenous infusion over 10-20 hours
• Given for 4 consecutive days per cycle
• Up to 5 cycles total

Combination therapy: 3

• Alternating cycles of GM-CSF and IL-2 with dinutuximab
• Plus 13-cis-retinoic acid (RA)
• Final cycle: RA alone 3

Critical premedication requirements: 3

• Intravenous opioid (morphine) prior to, during, and for 2 hours following completion of infusion due to severe neuropathic pain
• Required prehydration to prevent capillary leak syndrome
• Monitor closely for infusion reactions, hypotension, and neurotoxicity 3

Survival benefit: 3

• Demonstrated improvement in both event-free survival and overall survival compared to RA alone

Phase 5: Maintenance Therapy

13-cis-retinoic acid (RA) maintenance continues after immunotherapy completion 3

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Critical Management Caveats

MYCN Amplification:

• Overrides all other prognostic factors and automatically assigns high-risk status (except completely resected L1 tumors) 5
• If discovered after incomplete resection in presumed low-risk patient, immediately reassign to high-risk protocol 1

Age Considerations:

• All patients ≥18 months with stage M disease are high-risk regardless of other features 5
• Infants <6 months with small adrenal masses may be observed 1

Response Assessment Timing:

• End of induction: Critical for determining eligibility for consolidation 2
• Approximately 9% progress despite intensive induction regimens 2

International Classification Differences:

• Patients with L2, MYCN-nonamplified, >18 months with unfavorable histology are classified as high-risk by COG but may be intermediate-risk by European groups 5

Neurotoxicity Monitoring:

• Severe peripheral sensory neuropathy: 2-9% of patients receiving dinutuximab 3
• Permanently discontinue for severe unresponsive pain, severe sensory neuropathy, or moderate-to-severe peripheral motor neuropathy 3
• Rare but serious: prolonged urinary retention, transverse myelitis, reversible posterior leukoencephalopathy syndrome 3