What is the recommended treatment for neuroblastoma in a pediatric patient based on the risk group (low‑risk, intermediate‑risk, high‑risk) determined by age, stage, histology, MYCN status, and other biologic factors?

Treatment of Neuroblastoma

Neuroblastoma treatment is determined by risk stratification into low-risk, intermediate-risk, or high-risk groups based on age, INRG stage, MYCN amplification status, histology, segmental chromosomal aberrations, and ploidy—with treatment intensity ranging from observation alone for low-risk disease to intensive multimodality therapy for high-risk disease. 1

Risk Classification Framework

Risk assignment must occur before initiating therapy and integrates six prognostic factors: age at diagnosis, INRG stage (L1, L2, M, or MS), MYCN amplification status, histopathology (favorable vs. unfavorable per International Neuroblastoma Pathology Classification), presence of segmental chromosomal aberrations, and tumor ploidy status. 1, 2

Low-Risk Criteria

• Any age with L1 disease and MYCN non-amplified tumors 1, 2
• L1 disease with MYCN amplification ONLY if complete resection is achieved (residual disease upgrades to high-risk) 1, 2
• Infants <12 months with MS disease who have favorable histology, MYCN non-amplified, hyperdiploid tumors, and no segmental chromosomal aberrations 1, 2

High-Risk Criteria

• MYCN amplification supersedes all other factors and assigns high-risk status, except for completely resected L1 tumors 1, 2
• All patients ≥18 months with M-stage disease regardless of other biologic features 1, 2
• Patients 12-18 months with M or MS disease who have unfavorable histology, segmental chromosomal aberrations, or MYCN amplification 1, 2
• L2 disease in patients ≥18 months with MYCN non-amplified but unfavorable histology or undifferentiated/poorly differentiated tumors 1, 2

Intermediate-Risk Criteria

• Patients whose disease characteristics do not meet low-risk or high-risk criteria 1, 2
• Symptomatic infants with MS disease too ill for biopsy (coagulopathy, respiratory compromise from hepatomegaly) receive presumptive intermediate-risk therapy, with escalation to high-risk if MYCN amplification is later identified 1, 2

Treatment by Risk Group

Low-Risk Neuroblastoma Treatment

Five-year survival exceeds 95% with minimal intervention. 1, 3

• Surgical resection is the primary treatment for L1 tumors when it can be performed safely 1, 4
• Observation without biopsy is appropriate for infants <6 months with isolated adrenal masses ≤3.1 cm maximum diameter (or ≤5 cm if ≥25% cystic) 1
• No chemotherapy or radiation therapy is required for most low-risk patients 3
• Supplemental treatment is necessary in only 10% of patients with recurrence managed successfully with surgery or multimodality treatment 5

Intermediate-Risk Neuroblastoma Treatment

Five-year survival is 90-95% with moderate-intensity chemotherapy. 1, 3

• Administer 2-8 cycles of cyclophosphamide-based chemotherapy to achieve 90% tumor volume reduction 4, 6
• Delayed surgical resection follows chemotherapy 4, 6
• No radiation therapy is routinely indicated 3
• Supplemental treatment is necessary in approximately 20% of patients 5

High-Risk Neuroblastoma Treatment

Five-year survival is 50-62% despite intensive multimodality therapy. 3, 7

Intensive multimodality therapy consists of:

1. Induction chemotherapy with multiple cycles of combination chemotherapy 4, 6, 8
2. Surgical resection of the primary tumor 4, 6
3. Myeloablative consolidation with autologous hematopoietic stem cell transplantation 4, 6, 8
4. Local radiation therapy 4, 6
5. Immunotherapy with differentiation therapy as maintenance phase 4, 6, 8

Critical Treatment Pitfalls

If MYCN amplification is discovered after incomplete resection in a presumed low-risk patient, immediate reassignment to high-risk protocol is mandatory. 3 This represents a critical decision point where delayed recognition can compromise outcomes.

Approximately 9% of high-risk patients progress despite intensive induction regimens. 3 Early identification of non-responders is essential for consideration of alternative strategies.

Fertility preservation discussion must occur before chemotherapy initiation when possible, as treatment beyond 90 days of cyclophosphamide increases probability of sterility in males. 4

Essential Monitoring During Treatment

• CT or MRI of primary site prior to planned surgical resection 4
• Full disease evaluation at end of induction, start of post-consolidation, and end of therapy 4
• Serial monitoring of organ function including renal function, cardiac function, and hearing assessments 4
• 123I-MIBG scintigraphy is the primary modality for assessing metastatic disease, with FDG-PET mandated for MIBG-non-avid disease 2

Long-Term Surveillance

High-risk neuroblastoma survivors require lifelong monitoring for treatment-related complications including ototoxicity from platinum-based chemotherapy, cardiac dysfunction, fertility impairment, and second malignancies. 3 Survivors face significantly elevated risks of grade 3-5 chronic health conditions and second malignant neoplasms. 3

Multidisciplinary Team Requirements

Treatment decisions must involve diagnostic radiologists, nuclear medicine physicians, interventional radiologists, pediatric surgeons, anatomic and molecular pathologists, radiation oncologists, and pediatric oncologists. 1, 2

Clinical trial enrollment is strongly encouraged for all patients as trials continue to refine treatment strategies. 4