What is the management approach for a pediatric patient under 5 years old with neuroblastoma, based on the stage of the disease?

Neuroblastoma Stage-Based Management in Children Under 5 Years

Treatment for neuroblastoma in children under 5 years is determined by risk stratification using the International Neuroblastoma Risk Group Staging System (INRGSS), with low-risk patients receiving surgery alone or observation, intermediate-risk patients requiring 2-8 cycles of chemotherapy followed by surgery, and high-risk patients needing intensive multimodality therapy including induction chemotherapy, surgery, myeloablative consolidation with autologous stem cell transplant, radiation, immunotherapy with dinutuximab, and maintenance therapy. 1, 2

Risk Stratification Framework

Risk classification must occur before therapy initiation and integrates six key prognostic factors: 3

• Age at diagnosis (critical cutoff at 18 months) 3, 4
• INRG stage (L1, L2, M, or MS) 3
• MYCN amplification status (the single most powerful prognostic factor) 3
• Histopathology per International Neuroblastoma Pathology Classification 1, 3
• Segmental chromosomal aberrations (1p and 11q deletions) 3, 4
• Tumor ploidy (diploid vs hyperdiploid) 3, 4

Critical caveat: MYCN amplification overrides all other prognostic factors and mandates high-risk treatment, except for completely resected L1 tumors. 1, 2, 3 If MYCN amplification is discovered after incomplete resection in a presumed low-risk patient, immediately reassign to high-risk protocol. 2

Low-Risk Disease Management

5-year survival exceeds 95% with minimal intervention. 2

Treatment Approach:

• L1 tumors (localized, no image-defined risk factors): Surgical resection is the primary treatment when it can be performed safely with minimal morbidity 2
• Neonates and infants <6 months: Observation without biopsy is appropriate for isolated adrenal masses ≤3.1 cm if solid or ≤5 cm if ≥25% cystic 2
• MS disease (metastatic special) with favorable biology: Observation is the preferred approach for asymptomatic patients 2
• No chemotherapy or radiation is required for most low-risk patients 2

Monitoring Requirements:

• Serial imaging to document spontaneous regression or stability 5
• Urinary catecholamines (VMA/HVA) at diagnosis and follow-up 6
• 123I-MIBG scintigraphy for initial staging (uptake in 90-95% of cases) 3, 6

Intermediate-Risk Disease Management

5-year survival: 90-95%. 2

Chemotherapy Protocol:

• 2-8 cycles of chemotherapy based on age, stage, and biologic features 1, 2
• Cyclophosphamide-based regimens are standard 2
• Treatment goals vary by tumor biology: 2
  • Localized favorable biology: Achieve ≥50% reduction in primary tumor volume
  • Localized unfavorable biology: Continue therapy until 90% reduction in primary tumor volume

Surgical Approach:

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

Key Management Points:

• No radiation is routinely indicated for intermediate-risk disease 2
• Response assessment uses volume measurements or single-dimension RECIST criteria 2
• Monitor for chemotherapy-related toxicities including myelosuppression and organ dysfunction 7

High-Risk Disease Management

5-year survival: <50% despite intensive therapy. 3

Patient Criteria:

• All patients ≥18 months with stage M (metastatic) disease regardless of other features 2, 3
• Any age with MYCN amplification (except completely resected L1 tumors) 1, 2, 3
• Patients 12-18 months with stage M disease and unfavorable biology (unfavorable histology, segmental chromosomal aberrations, or diploid tumors) 4, 8

Multimodality Treatment Protocol:

Induction Phase:

• Intensive combination chemotherapy (typically 5-6 cycles) 7
• Anatomic imaging (CT or MRI) of primary site prior to planned surgical resection 7
• Full disease evaluation at end of induction: anatomic imaging, 123I-MIBG scan (or FDG-PET if MIBG nonavid), and bilateral bone marrow aspirates and biopsies 7

Surgical Resection:

• Maximum feasible surgical resection after induction chemotherapy 9
• Goal is gross total resection while preserving organ function 7

Consolidation Phase:

• Myeloablative consolidation chemotherapy followed by autologous stem cell transplant 9
• Detailed evaluation of renal function (nuclear medicine measurements of glomerular filtration rate) is essential before consolidation 7
• Radiation therapy to residual soft tissue disease 9
• Patients with >5 residual MIBG-avid sites at end of induction should have repeat scan after stem cell rescue to prioritize metastatic sites for radiotherapy 7

Immunotherapy Phase:

• Dinutuximab (Unituxin): 17.5 mg/m²/day IV infusion over 10-20 hours for 4 consecutive days, maximum of 5 cycles 9
• Administered in combination with GM-CSF, IL-2, and 13-cis-retinoic acid 9
• Required premedication: 9
  • IV hydration: 0.9% NaCl 10 mL/kg over 1 hour prior to each infusion
  • Morphine sulfate: 50 mcg/kg IV immediately prior, then 20-50 mcg/kg/hour during and for 2 hours after infusion
  • Antihistamine (diphenhydramine 0.5-1 mg/kg) 20 minutes prior and every 4-6 hours during infusion
  • Acetaminophen (10-15 mg/kg) 20 minutes prior and every 4-6 hours as needed

Maintenance Therapy:

• 13-cis-retinoic acid (isotretinoin) for 6 cycles 9
• Eflornithine as continuation therapy is a category 2B recommendation following completion of anti-GD2 immunotherapy 7

Critical Monitoring During High-Risk Therapy:

Disease Evaluations: 7

• Full disease evaluation at: end of induction, start of post-consolidation, and end of therapy
• 123I-MIBG scan (or FDG-PET if MIBG nonavid) halfway through post-consolidation therapy
• Response assessment uses revised INRC criteria (2017) based on RECIST criteria and semiquantitative scoring (modified Curie score) 7, 2

Organ Function Monitoring: 7

• Frequent laboratory monitoring: blood counts, chemistry panels, urinalyses
• Serial cardiac function: electrocardiograms and echocardiograms
• Serial hearing monitoring: audiograms or brainstem auditory evoked response (critical as most patients are at critical age for language development)
• Renal function assessment before consolidation

High-Risk Therapy Toxicities:

Severe neuropathic pain: Occurs in the majority of patients receiving dinutuximab 9

• Requires aggressive pain management with IV opioids
• Consider gabapentin or lidocaine if inadequately controlled with opioids alone 9

Peripheral neuropathy: Grade 3 peripheral sensory neuropathy occurs in 2-9% of patients 9

• Discontinue dinutuximab for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy 9

Ototoxicity: Most high-risk patients experience ototoxicity from platinum-based chemotherapy, with 13% developing new or worsening hearing loss after eflornithine initiation 2

Infusion reactions: Serious and potentially life-threatening infusion reactions occur in 26% of patients treated with dinutuximab 9

• Monitor closely during and for at least 4 hours following each infusion
• Immediately interrupt for severe reactions; permanently discontinue for anaphylaxis 9

Special Populations and Considerations

Stage MS Disease (Metastatic Special):

• Unique pattern of disseminated disease in infants <18 months with metastases limited to skin, liver, and/or bone marrow (<10% tumor cells) 5
• Can be challenging to manage and may require early intervention with systemic chemotherapy if symptomatic 5
• Asymptomatic patients with favorable biology can be observed 2

Adolescents and Adults:

• Clinical studies predominantly included patients <5 years at diagnosis 7
• General principles of high-risk therapy should be applied, though may require individualized approach based on comorbid conditions and treatment tolerance 7

Patients 12-18 Months Old:

• The 2006 COG reclassification raised the age cutoff for high-risk assignment from 12 to 18 months 8
• Toddlers 12-18 months with stage 4, MYCN-NA, favorable histology, hyperdiploid tumors now receive intermediate-risk therapy with excellent outcomes (5-year EFS/OS: 87-88%/94-95%) 8
• This assigned reduction in therapy maintains excellent outcomes while avoiding acute toxicity and late effects of high-risk regimens 8

Essential Molecular Testing

Before initiating therapy, obtain: 1, 3

• MYCN amplification status (mandatory in all cases)
• Segmental chromosomal aberrations (1p and 11q deletions)
• Tumor cell ploidy (DNA index)
• ALK gene amplification/mutations (ALK inhibitors available for actionable mutations) 2
• Histology classification per International Neuroblastoma Pathology Classification

Critical Staging Requirements

Imaging: 3

• 123I-MIBG scintigraphy is the primary imaging modality (uptake in up to 90% of neuroblastomas) 3, 6
• FDG-PET imaging is mandatory for MIBG-nonavid disease or suspected mixed-avidity disease 3
• Exception: Patients <6 months with L1 adrenal tumors ≤3.1 cm if solid or ≤5 cm if ≥25% cystic 3

Bone Marrow Assessment: 7, 3

• Bilateral aspirates and core biopsies using conventional morphology for initial staging
• 10% tumor cell infiltration distinguishes stage M from MS disease 7
• More sensitive methods (immunocytology, QRT-PCR) reserved for minimal residual disease detection during or after therapy 7

Long-Term Considerations

Fertility Preservation: Discuss before chemotherapy initiation when possible 2

Late Effects Monitoring: Survivors of high-risk neuroblastoma face significantly elevated risks of: 2

• Grade 3-5 chronic health conditions
• Second malignant neoplasms
• Treatment-related organ dysfunction (cardiac, renal, hearing loss)

Clinical Trial Enrollment: Strongly encouraged for all patients, as trials continue to refine treatment strategies and identify new therapeutic approaches 1, 2