What is the treatment plan for a pediatric patient diagnosed with neuroblastoma, considering the stage of the disease and overall health?

Neuroblastoma Staging and Treatment

Staging System

Use the International Neuroblastoma Risk Group (INRG) Staging System to classify disease before initiating treatment. 1

• L1 tumors: Localized disease confined to one body compartment without involvement of vital structures (no image-defined risk factors present) 1
• L2 tumors: Locoregional disease with one or more image-defined risk factors present 1
• M stage: Distant metastatic disease (except MS) 1
• MS stage: Metastases confined to skin, liver, and/or bone marrow (limited marrow disease) in children <18 months of age only 1

Risk Classification

Risk stratification must occur before therapy initiation and integrates six key prognostic factors: age at diagnosis, INRG stage, MYCN amplification status, histopathology (favorable vs unfavorable per International Neuroblastoma Pathology Classification), segmental chromosomal aberrations, and tumor ploidy. 2

Critical Rule: MYCN Amplification Override

MYCN amplification overrides all other prognostic factors and mandates high-risk treatment, with the sole exception of completely resected L1 tumors. 3, 2 If incomplete resection reveals MYCN amplification in a presumed low-risk patient, immediately reassign to high-risk protocol. 4

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Low-Risk Disease Treatment

Low-risk patients (L1 MYCN-nonamplified tumors, or asymptomatic MS disease <12 months with favorable biology) achieve >95% 5-year survival with surgery alone or observation. 3, 2

Specific Treatment Approach:

• Surgical resection is primary treatment when it can be performed safely with minimal morbidity 4
• Observation without biopsy is appropriate for infants <6 months with isolated adrenal masses ≤3.1 cm if solid or ≤5 cm if ≥25% cystic 1, 4
• No chemotherapy or radiation required for most low-risk patients 4
• For asymptomatic INRG MS disease with favorable biology (MYCN-nonamplified, hyperdiploid, without segmental chromosomal aberrations), observation is preferred 1, 4

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Intermediate-Risk Disease Treatment

Intermediate-risk patients (primarily unresectable/symptomatic L2/L3 disease and infants with Stage M disease) achieve 90-95% 5-year survival with 2-8 cycles of chemotherapy followed by surgery. 3, 2

Treatment Algorithm:

1. Administer cyclophosphamide-based chemotherapy regimens 2
2. Number of cycles determined by: disease stage, age at diagnosis, and biologic features 4
3. Treatment goals vary by tumor biology: 4
   • Localized favorable biology: Achieve ≥50% reduction in primary tumor volume
   • Localized unfavorable biology: Continue therapy until 90% reduction in primary tumor volume
4. Surgical resection after achieving target tumor reduction 4
5. Preservation of vital structures and end-organ function is paramount—less than complete resection is acceptable 2, 4
6. If chemotherapy results in <50% tumor reduction, consider surgery; if surgery cannot be performed safely, give additional chemotherapy with re-evaluation every 2 cycles 4
7. No radiation routinely indicated for intermediate-risk disease 4

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High-Risk Disease Treatment

High-risk patients (<50% 5-year survival) require intensive multimodality therapy including induction chemotherapy, surgery, myeloablative consolidation with autologous stem cell transplant, radiation, immunotherapy with dinutuximab, and maintenance therapy. 3, 2

High-Risk Criteria:

• All patients ≥18 months with stage M disease regardless of other features 4
• Patients 12-18 months with M or MS disease with unfavorable histology, segmental chromosomal aberrations, or MYCN amplification 1
• L1 disease with MYCN amplification and residual tumor post-resection 1

Treatment Protocol:

1. Induction chemotherapy: Intensive multi-agent regimens 2
2. Surgical resection: After induction, aiming for >90% tumor reduction 5
3. Myeloablative consolidation with autologous stem cell transplant 2
4. Radiation therapy 2
5. Immunotherapy with dinutuximab (FDA-approved in combination with GM-CSF, IL-2, and 13-cis-retinoic acid for high-risk neuroblastoma achieving at least partial response to first-line therapy) 6
6. Maintenance therapy 2

Critical Monitoring:

• Full disease evaluation required at end of induction, start of post-consolidation, and end of therapy using revised International Neuroblastoma Response Criteria and modified Curie score for 123I-MIBG imaging 2
• Serial cardiac function assessment and audiological monitoring due to treatment toxicity (most patients experience ototoxicity from platinum-based chemotherapy) 4
• Discuss fertility preservation before chemotherapy initiation when possible 2

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Essential Molecular Testing Requirements

Obtain molecular genetic testing before initiating therapy to guide risk stratification, including: 3, 2

• MYCN amplification status
• Segmental chromosomal aberrations (1p deletion, 11q deletion, 17q gain, plus 3p, 4p, 10q, 14q aberrations) 1
• Tumor cell ploidy (DNA index)
• ALK gene amplification/mutations (to guide targeted therapy selection) 2, 4
• Histology classification per International Neuroblastoma Pathology Classification

Next-generation sequencing is recommended as it can simultaneously evaluate all key prognostic factors and identify actionable mutations, which is beneficial when tissue is limited. 1, 4

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Imaging and Staging Workup

• 123I-MIBG scintigraphy is the primary functional imaging modality 2
• FDG-PET imaging mandatory for MIBG-nonavid disease or suspected mixed-avidity disease 2
• Cross-sectional imaging (MRI with/without contrast or CT with contrast) to evaluate soft tissue disease 1
• Bilateral bone marrow aspirates and core biopsies required for initial staging (10% tumor cell infiltration distinguishes stage M from MS disease) 2

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Common Pitfalls

• Never delay risk classification for molecular testing results—these are essential for appropriate treatment assignment 3
• Do not pursue aggressive resection in intermediate-risk disease if it compromises vital organ function 2
• Recognize that approximately 9% of high-risk patients progress despite intensive induction regimens—end of induction evaluation is critical for determining consolidation eligibility 4
• Survivors of high-risk neuroblastoma face significantly elevated risks of grade 3-5 chronic health conditions, second malignant neoplasms, and treatment-related organ dysfunction requiring lifelong surveillance 2, 4

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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. 3, 4