What are the current treatment options for high-risk neuroblastoma?

Updates on the Management of High-Risk Neuroblastoma

The current standard treatment for high-risk neuroblastoma consists of a four-phase approach: intensive induction chemotherapy (ANBL12P1 or ANBL1531 protocols with topotecan/cyclophosphamide-based regimens), consolidation with tandem autologous stem cell transplantation, post-consolidation immunotherapy with anti-GD2 antibody (dinutuximab) plus GM-CSF and isotretinoin, and continuation therapy with eflornithine for responders. 1

Induction Chemotherapy

Preferred Regimen:

• The NCCN recommends 5 cycles of ANBL12P1 or ANBL1531 protocols, achieving approximately 80% partial response or better 2, 3
• Cycles 1-2: Topotecan (1.2 mg/m²/day) + cyclophosphamide (400 mg/m²/day) for 5 days 2, 3
• Cycles 3 and 5: Cisplatin (50 mg/m²/day for 4 days) + etoposide (200 mg/m²/day for 3 days) 2
• Cycles 4 and 6: Cyclophosphamide (2100 mg/m²/day for 2 days) + doxorubicin (25 mg/m²/day) + vincristine (0.67 mg/m²/day for 3 days) 2

Surgical Timing:

• Perform surgical resection after several cycles of cytoreductive chemotherapy, not upfront 1
• Goal is gross total resection (>90% tumor removal or complete macroscopic resection), not negative margins 1
• Accept subtotal resection when vital organs, major nerves, or major blood vessels would be compromised 1

Critical Pitfall: Do not attempt upfront resection or pursue negative margins at the expense of vital structures 1

End-Induction Response Assessment and Decision Points

For Partial Response or Better:

• Proceed directly to consolidation with tandem transplantation 1
• Consider bridging therapy for select patients with marginal partial response 1

For Minor Response or Stable Disease:

• Switch to alternative chemotherapy regimens (high-dose cyclophosphamide-based or topotecan-containing) 2
• Reassess after every 2 cycles to determine if adequate response achieved for consolidation 2
• If still inadequate, consider chemoimmunotherapy (anti-GD2 + chemotherapy) or clinical trial enrollment 1

For Progressive Disease:

• Do NOT proceed to consolidation therapy 1
• Initiate chemoimmunotherapy combining anti-GD2 monoclonal antibody with chemotherapy 1
• Consider clinical trial enrollment for first relapse 1

Critical Pitfall: Do not continue the same failing regimen beyond 2 cycles without modification 2

Consolidation Therapy

Tandem Transplantation (Preferred):

• First transplant: Thiotepa/cyclophosphamide 1
• Second transplant (6-10 weeks later): Dose-reduced carboplatin/etoposide/melphalan (CEM) 1
• Outcome: 3-year EFS of 61.6% vs 48.4% with single transplant 1, 3

Alternative Regimen:

• Busulfan/melphalan (BuMel) is preferred in Europe with superior EFS compared to CEM, but higher risk of sinusoidal obstruction syndrome 1
• May be appropriate for patients with contraindication to tandem transplant 1

Single Transplant Exceptions: Two specific subgroups may receive single transplant with full-dose CEM (5-year EFS 75-80%): 1

1. Stage L2, ≥18 months at diagnosis, unfavorable histology, AND MYCN non-amplified
2. Stage M, 12 to <18 months at diagnosis, MYCN non-amplified, with unfavorable histology, diploid DNA, or segmental chromosomal aberrations

Radiation Therapy:

• Administer 21.6 Gy to primary tumor site after recovery from stem cell rescue 1
• Include sites of residual metastatic disease visible on ¹²³I-MIBG or FDG-PET at end-induction evaluation 1
• Do NOT extend fields to uninvolved draining nodes (no benefit demonstrated) 1
• Do NOT boost gross residual tumor beyond 21.6 Gy (no benefit demonstrated) 1

Post-Consolidation Immunotherapy

Standard Regimen:

• Dinutuximab (anti-GD2 antibody) + GM-CSF (sargramostim) + isotretinoin for up to 5 cycles 1, 4
• 2-year EFS: 66% vs 46% with isotretinoin alone 5
• Do NOT add interleukin-2 (increased toxicity without improved outcomes) 1

Alternative:

• Dinutuximab beta + isotretinoin without sargramostim (European approach) shows higher EFS than isotretinoin alone 1

FDA-Approved Indication: Dinutuximab is indicated in combination with GM-CSF, IL-2, and isotretinoin for pediatric patients with high-risk neuroblastoma achieving at least partial response to prior first-line therapy 4

Continuation Therapy

Eflornithine (FDA-approved December 2023):

• Dose: 750 mg/m² ± 250 mg/m² twice daily for up to 2 years 1
• Indication: Patients achieving partial response or better following anti-GD2 immunotherapy 1
• Outcomes: EFS HR 0.48 (95% CI 0.27-0.85); OS HR 0.32 (95% CI 0.15-0.70) compared to historical controls 1
• NCCN Category 2B recommendation: Discuss as continuation therapy option with families 1

Critical Monitoring: Serial audiograms or brainstem auditory evoked response testing is essential due to ototoxicity risk during critical language development age 1

Monitoring During Treatment

Disease Evaluations:

• Full assessment (CT/MRI, ¹²³I-MIBG or FDG-PET, bilateral bone marrow biopsies) at: end of induction, start of post-consolidation, and end of therapy 1
• For >5 residual MIBG-avid sites at end-induction: repeat scan after stem cell rescue to prioritize radiotherapy targets 1

Organ Function Monitoring:

• Renal function with nuclear medicine GFR measurements before consolidation 1, 3
• Serial ECGs and echocardiograms for cardiac function 1, 3
• Serial audiograms or brainstem auditory evoked response for hearing 1, 3
• Frequent blood counts, chemistry panels, and urinalyses 1

Key Algorithmic Decision Points

1. After induction: Partial response or better → tandem transplant; minor response/stable → alternative chemotherapy with reassessment every 2 cycles; progressive disease → chemoimmunotherapy or clinical trial 1, 2

2. After consolidation: No progression → anti-GD2 immunotherapy; progression → chemoimmunotherapy or clinical trial 1

3. After immunotherapy: Partial response or better → discuss eflornithine continuation 1

Critical Pitfall: The evidence does NOT support extending induction beyond standard protocols—adding topotecan courses increases toxicity without improving EFS 6