What is the recommended treatment approach for neuroblastoma in children under 5 years old?

Treatment Approach for Neuroblastoma in Children Under 5 Years

Risk-Based Treatment Strategy

Treatment for neuroblastoma in children under 5 years is determined by risk stratification based on stage, age, histology, MYCN amplification status, and segmental chromosomal aberrations—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 chemotherapy, surgery, radiation, autologous stem cell transplant, immunotherapy with dinutuximab, and maintenance therapy. 1, 2

Essential Molecular Testing Before Treatment

Before initiating any treatment, obtain molecular genetic testing to guide risk stratification 1:

• MYCN amplification status (most critical prognostic factor—amplification automatically assigns high-risk status except for completely resected L1 tumors) 1, 2
• Segmental chromosomal aberrations (loss of 1p, 11q, 3p, 4p; gain of 17q, 1q, 2p) 1
• Tumor cell ploidy (DNA index >1 is more favorable than DNA index = 1) 1
• ALK gene amplification/mutations (predicts response to targeted ALK inhibitors) 1, 2
• Histology classification per International Neuroblastoma Pathology Classification (favorable vs. unfavorable based on differentiation, mitosis-karyorrhexis index, and age) 1

Low-Risk Disease Management

For INRG L1 tumors with favorable biology 2:

• Infants <6 months with isolated adrenal masses: Observation alone without biopsy if mass is ≤3.1 cm (solid) or ≤5 cm (≥25% cystic) 2
• Resectable tumors: Surgical resection alone when safe with minimal morbidity 2
• Asymptomatic INRG MS disease with favorable biology: Observation preferred 2
• No chemotherapy or radiation required for most low-risk patients 2
• Expected 5-year survival >95% 2

Critical caveat: If incomplete resection reveals MYCN amplification, immediately reassign to high-risk protocol 2

Intermediate-Risk Disease Management

Treatment sequence for intermediate-risk patients 2:

Induction Chemotherapy

• 2-8 cycles of cyclophosphamide-based chemotherapy (number determined by stage, age, and biology) 2
• Target tumor reduction: ≥50% for favorable biology; 90% for unfavorable biology 2
• Response assessment every 2 cycles using volume measurements or RECIST criteria 2

Surgery Timing and Approach

• Perform surgery after achieving target tumor reduction 2
• Preservation of vital structures and end-organ function is paramount—less than complete resection is acceptable 2
• If chemotherapy achieves <50% reduction, consider surgery if feasible 2
• If surgery cannot be performed safely, continue chemotherapy with re-evaluation every 2 cycles 2

Radiation

• No radiation routinely indicated for intermediate-risk disease 2

Expected 5-year survival: 90-95% 2

High-Risk Disease Management

High-risk patients (includes all children ≥18 months with stage M disease, any age with MYCN amplification) require intensive multimodality therapy 2, 3:

Treatment Components

• Intensive induction chemotherapy (multiple cycles) 2
• Maximal safe surgical resection after chemotherapy response 2
• Myeloablative consolidation chemotherapy followed by autologous stem cell transplant 3
• Radiation therapy to residual soft tissue disease 3, 4
• Immunotherapy with dinutuximab (up to 5 cycles in combination with GM-CSF and IL-2, alternating with 13-cis-retinoic acid) 3
• Maintenance therapy with 13-cis-retinoic acid 3

Dinutuximab Administration

Dinutuximab is FDA-approved for high-risk neuroblastoma as part of multimodality therapy in pediatric patients (studied in ages 11 months to 15 years) 3:

• Administered after patients achieve at least partial response to first-line therapy 3
• Requires morphine for pain management during infusion 3
• Monitor for nerve fiber degeneration (peripheral neuropathy risk) 3

Monitoring Requirements

• Serial cardiac function assessment (due to anthracycline cardiotoxicity) 2
• Audiological monitoring (most patients experience ototoxicity from platinum-based chemotherapy; 13% develop new/worsening hearing loss after eflornithine) 2
• Fertility preservation discussion before chemotherapy initiation 2

Response Evaluation

Use revised International Neuroblastoma Response Criteria (2017) 2:

• RECIST criteria for anatomic imaging 2
• Modified Curie score for 123I-MIBG functional imaging 2, 5

Diagnostic Imaging Requirements

Essential imaging studies for staging and monitoring 5, 6:

• CT or MRI of primary site (defines local extent, vascular encasement) 6
• 123I-MIBG scintigraphy (accumulates in 90-95% of neuroblastomas; detects primary tumor and metastases in bone, bone marrow, lymph nodes, soft tissues) 5, 6
• 99mTc-disphosphonate bone scintigraphy (for skeletal metastases) 5
• Bone marrow aspiration and biopsy (bilateral samples required) 6
• Urine catecholamine measurements (elevated in >90% of cases) 6

Special Considerations for Neonates

Neonatal neuroblastoma (diagnosed in first 28 days of life) has favorable prognosis 7:

• Watch-and-wait approach emphasized for low-risk patients due to high rate of spontaneous regression 7
• Stage MS disease (unique disseminated pattern in infants) may require early systemic chemotherapy if symptomatic 7
• Minimize therapy to reduce toxicities whenever possible 7

Critical Management Pitfalls to Avoid

• Never underestimate MYCN amplification: It overrides all other prognostic factors and mandates high-risk treatment (except completely resected L1 tumors) 1, 2
• Do not delay molecular testing: Results are essential for appropriate risk assignment before initiating therapy 1
• Avoid aggressive surgery in intermediate-risk disease: Preservation of organ function takes precedence over complete resection 2
• Do not miss stage MS disease in infants: This unique presentation requires different management than typical metastatic disease 7
• Ensure adequate pain management during dinutuximab: Morphine is required during infusion 3

Clinical Trial Enrollment

Strongly encourage enrollment in molecular classification-based clinical trials for all patients, as trials continue to refine treatment strategies and identify new therapeutic approaches 2