What are the staging and treatment approaches for neuroblastoma in pediatric patients?

Neuroblastoma Staging and Treatment in Children

Children with neuroblastoma should be staged using the International Neuroblastoma Risk Group Staging System (INRGSS) before treatment initiation, with risk-stratified therapy ranging from observation alone for low-risk disease to intensive multimodality therapy for high-risk disease, as this approach achieves >95% survival in low-risk patients and optimizes outcomes across all risk groups. 1, 2

Staging System

The INRGSS must be completed before any treatment begins, as it forms the foundation for risk classification and directly determines treatment intensity 1, 3. This system classifies tumors into four stages based on imaging findings rather than surgical findings 1, 4:

• L1 (Localized): Tumor confined to one body compartment without involvement of vital structures, as defined by absence of image-defined risk factors (IDRFs) 1
• L2 (Locoregional): Tumor with presence of one or more IDRFs indicating proximity to or involvement of vital structures 1
• M (Metastatic): Distant metastatic disease 1
• MS (Metastatic Special): Only in children <18 months with metastases confined to skin, liver, and/or bone marrow (limited marrow involvement <10% tumor cells) 1

Required Staging Workup

Imaging studies 1:

• Cross-sectional imaging (MRI with/without contrast or CT with contrast) for soft tissue disease evaluation
• MRI spine with/without contrast for paraspinal tumors or suspected spinal involvement
• ¹²³I-MIBG scintigraphy as primary imaging for metastatic disease (detects up to 90% of neuroblastomas) 1
• ¹⁸F-FDG-PET for MIBG-nonavid or mixed-avidity disease, except in infants <6 months with small L1 adrenal tumors (≤3.1 cm if solid or ≤5 cm if ≥25% cystic) 1

Bone marrow assessment 1:

• Bilateral bone marrow aspirates and core biopsies using conventional morphology for initial staging
• 10% tumor cell infiltration is the critical threshold distinguishing M from MS disease 1
• More sensitive methods (immunocytology, qRT-PCR) reserved for minimal residual disease detection during/after therapy 1

Molecular testing (essential before treatment) 1, 3, 5:

• MYCN amplification status (most powerful prognostic factor)
• Segmental chromosomal aberrations (1p deletion, 11q aberration)
• Tumor cell ploidy (diploid vs. hyperdiploid)
• ALK gene amplification/mutations
• Histology classification per International Neuroblastoma Pathology Classification

Risk Classification

The Children's Oncology Group (COG) 2021 risk classification integrates six prognostic factors: age at diagnosis, INRG stage, MYCN status, histopathology, segmental chromosomal aberrations, and ploidy 1, 3, 6. Patients are classified into three risk groups with dramatically different survival outcomes 2, 3, 6:

• Low-risk: 5-year survival >95%
• Intermediate-risk: 5-year survival 90-95%
• High-risk: 5-year survival <50%

Critical Risk Assignment Rules

MYCN amplification overrides nearly all other factors and mandates high-risk classification, except for completely resected L1 tumors 2, 3, 5. If MYCN amplification is discovered after incomplete resection in a presumed low-risk patient, immediately reassign to high-risk protocol 2.

All patients ≥18 months with M stage disease are automatically high-risk regardless of any other features 2, 3.

International variation exists: Patients with L2, MYCN-nonamplified disease who are >18 months with unfavorable histology are classified as high-risk by COG criteria but may be intermediate-risk by European groups 3.

Treatment by Risk Group

Low-Risk Disease

Surgery alone or observation is the standard approach, with >95% 5-year survival 2, 5:

• L1 tumors: Surgical resection when feasible with minimal morbidity 2
• Select neonates: Observation without biopsy for infants <6 months with isolated adrenal masses ≤3.1 cm if solid or ≤5 cm if ≥25% cystic 2, 5
• Asymptomatic MS disease with favorable biology: Observation is preferred 2
• No chemotherapy or radiation required for most low-risk patients 2

Intermediate-Risk Disease

Treatment requires 2-8 cycles of chemotherapy followed by surgery, achieving 90-95% 5-year survival 2, 5:

Chemotherapy regimen 2:

• Cyclophosphamide-based regimens are standard
• Number of cycles determined by disease stage, age, and biologic features
• Target tumor reduction: ≥50% for favorable biology tumors; 90% for unfavorable biology tumors
• Response assessed using RECIST criteria or volume measurements

Surgical approach 2:

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

No radiation routinely indicated 2

High-Risk Disease

Intensive multimodality therapy is required 2, 5, 7:

Induction chemotherapy 2:

• Intensive multi-agent regimens
• Approximately 9% progress despite intensive induction

Surgery 2:

• Maximum feasible resection after induction

Consolidation 2:

• Myeloablative chemotherapy followed by autologous stem cell transplant
• Radiation therapy to residual soft tissue disease

Immunotherapy 7:

• Dinutuximab (Unituxin) is FDA-approved in combination with GM-CSF, IL-2, and 13-cis-retinoic acid for pediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy 7
• Dose: 17.5 mg/m²/day IV over 10-20 hours for 4 consecutive days, maximum 5 cycles 7
• Required premedication: IV morphine (50 mcg/kg bolus then 20-50 mcg/kg/hour infusion), antihistamines, acetaminophen, IV hydration 7
• Major toxicities: Serious infusion reactions (26%), severe neuropathic pain (majority of patients), peripheral neuropathy 7

Maintenance therapy 2:

• 13-cis-retinoic acid

Critical Management Caveats

Timing considerations 1:

• Staging must be completed before treatment initiation when possible
• Emergent therapy should not be delayed for ¹²³I-MIBG or FDG-PET imaging, but obtain as soon as possible

Bone marrow threshold 1:

• The 10% tumor cell infiltration cutoff distinguishing M from MS disease can be achieved using conventional cytology
• Conventional methods have limited sensitivity for minimal disease detection

Treatment toxicity monitoring 2:

• Serial cardiac function assessment required for high-risk patients
• Audiological monitoring (13% develop new/worsening hearing loss after eflornithine)
• Fertility preservation discussion before chemotherapy initiation

Clinical trial enrollment strongly encouraged for all patients, as trials continue to refine treatment strategies 2, 5.