What is the initial treatment approach for a child diagnosed with stage 3 Neuroblastoma?

Initial Treatment Approach for Stage 3 Neuroblastoma

Stage 3 neuroblastoma requires risk-stratified treatment based on age, MYCN status, and tumor biology, with most patients receiving multiagent chemotherapy followed by delayed surgical resection, while MYCN-amplified tumors mandate high-risk intensive multimodality therapy regardless of other factors. 1, 2

Immediate Risk Classification Requirements

Before initiating any therapy, obtain comprehensive molecular testing to determine the appropriate treatment pathway 1:

• MYCN amplification status (most critical prognostic factor) 1
• Segmental chromosomal aberrations (1p, 11q, 3p, 4p, 17q, 1q, 2p) 1
• Tumor cell ploidy 1
• ALK gene amplification/mutations 1
• Histopathology per International Neuroblastoma Pathology Classification 1

Critical caveat: MYCN amplification overrides all other prognostic factors and automatically assigns high-risk status, except for completely resected L1 tumors. If discovered after incomplete resection in a presumed low-risk patient, immediately reassign to high-risk protocol. 2, 3, 4

Treatment Algorithm by Risk Group

Low-Risk Stage 3 (Favorable Biology, No MYCN Amplification, Age <18 months)

Surgical resection is the primary treatment when it can be performed safely with minimal morbidity. 2, 3

• Proceed directly to surgery if resection is feasible without threatening vital organs, major nerves, or blood vessels 1
• No chemotherapy or radiation required for most low-risk patients 3
• 5-year survival exceeds 95% with this approach 2, 3

Intermediate-Risk Stage 3 (Unfavorable Biology Without MYCN Amplification)

Administer 2-8 cycles of cyclophosphamide-based chemotherapy to achieve 90% tumor volume reduction, followed by delayed surgical resection. 1, 2, 3

Chemotherapy regimen:

• Cyclophosphamide-based combinations are standard 3
• Continue therapy until achieving 90% reduction in primary tumor volume for unfavorable biology tumors 3
• Reassess tumor response every 2 cycles using volume measurements or RECIST criteria 3

Surgical timing and approach:

• Perform surgery after achieving target tumor reduction 3
• Preservation of vital structures and end-organ function is paramount; less than complete resection is acceptable 3
• If surgery cannot be performed safely after initial chemotherapy, give additional cycles with re-evaluation every 2 cycles 3

Expected outcomes:

• 5-year survival: 90-95% 2, 3
• No radiation routinely indicated 3

High-Risk Stage 3 (MYCN-Amplified or Age ≥18 months with Unfavorable Features)

Intensive multimodality therapy is mandatory, consisting of induction chemotherapy, surgical resection, myeloablative consolidation with autologous stem cell transplant, radiation therapy, and immunotherapy. 1, 2

Phase 1: Induction Chemotherapy (5-6 cycles)

Preferred regimens (NCCN Category 1 recommendation) 1:

• ANBL12P1 or ANBL1531 protocols (5 cycles) as preferred regimens
• ANBL0532 protocol (6 cycles) as acceptable alternative
• Topotecan and cyclophosphamide in cycles 1-2, followed by cisplatin-based combinations

Induction goals:

• Achieve approximately 80% partial response or better 1
• Cytoreduction to facilitate subsequent surgical resection 1
• Full disease reassessment at end of induction using anatomic imaging, 123I-MIBG scan (or FDG-PET if MIBG-nonavid), and bilateral bone marrow aspirates/biopsies 1

Common pitfall: Approximately 9% of patients progress despite intensive induction regimens, requiring immediate protocol adjustment. 3

Phase 2: Surgical Resection

Timing: After several cycles of cytoreductive chemotherapy 1

Surgical goal: Gross total resection (>90% resection or complete macroscopic resection) 1

• When vital organs, major nerves, or major blood vessels would be threatened, perform subtotal resection instead 1
• Negative margins are rarely feasible and not the recommended goal 1

Phase 3: Consolidation

High-dose chemotherapy with autologous stem cell rescue 2

• Requires detailed renal function evaluation (nuclear medicine GFR measurements) before consolidation 1
• Serial cardiac monitoring with ECG and echocardiograms mandatory 1

Radiation therapy to primary tumor bed 2

Phase 4: Post-Consolidation Immunotherapy (Category 1 Recommendation)

Anti-GD2 monoclonal antibody therapy with dinutuximab plus sargramostim and isotretinoin 1

• This regimen demonstrated 2-year EFS of 66% versus 46% with isotretinoin alone 1
• Interleukin-2 is no longer recommended based on SIOPEN HR-NBL1 trial showing no benefit and increased toxicity 1
• Alternative: Dinutuximab beta with isotretinoin (without sargramostim) is acceptable 1

Phase 5: Continuation Therapy (Category 2B Recommendation)

Eflornithine (FDA-approved December 2023) for patients achieving partial response or better 1

• Dosing: 750 mg/m² ± 250 mg/m² twice daily for up to 2 years 1
• Demonstrated superior outcomes: EFS HR 0.48 (95% CI 0.27-0.85), OS HR 0.32 (95% CI 0.15-0.70) 1
• Critical monitoring: Serial audiograms or brainstem auditory evoked response essential, as most patients are at critical age for language development 1
• Reported adverse events: transaminitis and hearing loss 1

Expected outcomes for high-risk disease:

• 5-year survival <50% despite intensive therapy 3
• Survivors face significantly elevated risks of grade 3-5 chronic health conditions, second malignant neoplasms, and treatment-related organ dysfunction 1, 3

Essential Monitoring During Treatment

Disease evaluation schedule 1:

• CT or MRI of primary site prior to planned surgical resection
• Full disease evaluation at: end of induction, start of post-consolidation, and end of therapy
• For patients with >5 residual MIBG-avid sites at end of induction: repeat 123I-MIBG scan after stem cell rescue
• Halfway through post-consolidation: 123I-MIBG scan (or FDG-PET if MIBG-nonavid)

Organ function monitoring 1:

• Frequent blood counts, chemistry panels, urinalyses
• Renal function (nuclear medicine GFR) before consolidation
• Serial cardiac function (ECG, echocardiograms)
• Serial hearing assessments (audiograms or brainstem auditory evoked response)

Critical Pre-Treatment Counseling

Fertility preservation discussion should occur before chemotherapy initiation when possible. 3

• Treatment beyond 90 days of cyclophosphamide increases probability of sterility in males 5

Clinical trial enrollment is strongly encouraged for all patients, as trials continue to refine treatment strategies. 3, 4