What is the recommended treatment protocol for high‑risk neuroblastoma in adult patients?

Treatment Protocol for High-Risk Neuroblastoma in Adults

Adults with high-risk neuroblastoma should be treated following the same intensive multimodal protocol used in pediatric patients, consisting of induction chemotherapy with surgical resection, tandem autologous stem cell transplantation for consolidation, and postconsolidation anti-GD2 immunotherapy, though treatment must be individualized based on tolerance and comorbidities. 1

Treatment Framework

The treatment protocol follows three distinct phases:

1. Induction Therapy

Goal: Achieve maximal disease reduction before consolidation

• Multiagent chemotherapy using cisplatin- and alkylator-intensive regimens (approximately 6 cycles)

  • Topotecan/cyclophosphamide combinations are commonly used in cycles 1-2
  • Approximately 80% of patients achieve partial response or better 1
  • ~9% progress despite intensive therapy 1

• Surgical resection of primary tumor and locoregional disease during or after induction

• Stem cell collection during induction for subsequent transplantation

• End-induction evaluation includes:

  • Anatomic imaging (CT/MRI) of primary site
  • ¹²³I-MIBG scan (or FDG-PET if MIBG-nonavid)
  • Bilateral bone marrow aspirates and biopsies 1

Proceed to consolidation if partial response or better is achieved. Patients with progressive disease should receive chemoimmunotherapy (anti-GD2 antibody combined with chemotherapy) or enroll in clinical trials 1

2. Consolidation Therapy

Tandem transplantation is the Category 1 recommendation for most patients based on the COG ANBL0532 trial showing superior 3-year event-free survival (61.6% vs 48.4% for single transplant). 1

Regimen:

• First transplant: Thiotepa/cyclophosphamide
• Second transplant: Dose-reduced carboplatin/etoposide/melphalan (CEM) given 6-10 weeks later 1

Alternative for contraindications to tandem transplant:

• Single transplant with busulfan/melphalan (BuMel) - the European standard 1
• Single transplant with full-dose CEM

Radiation therapy:

• 21.6 Gy to primary tumor site after recovery from stem cell rescue 1
• Radiation to residual metastatic sites identified on end-induction ¹²³I-MIBG or FDG-PET (North American standard) 1
• Do NOT extend fields to uninvolved nodal stations (no benefit demonstrated) 1
• Do NOT boost gross residual tumor beyond 21.6 Gy (no benefit demonstrated) 1

3. Postconsolidation Therapy

Anti-GD2 immunotherapy is Category 1 recommendation for patients without disease progression after consolidation. 1

Preferred regimen:

• Dinutuximab + sargramostim (cycles 1,3,5) + isotretinoin
• Do NOT include interleukin-2 (no benefit, increased toxicity per SIOPEN HR-NBL1 trial) 1

Alternative:

• Dinutuximab beta + isotretinoin (without sargramostim) - European approach 1

Continuation therapy (Category 2B):

• Eflornithine 750 mg/m² twice daily for up to 2 years after completing anti-GD2 immunotherapy (FDA-approved December 2023) 1
• Study 3b showed improved outcomes (EFS HR 0.48, OS HR 0.32) compared to historical controls 1
• Monitor for transaminitis and hearing loss 1

Critical Monitoring Requirements

During treatment:

• Frequent blood counts, chemistry panels, urinalyses
• Glomerular filtration rate before high-dose chemotherapy
• Serial echocardiograms and electrocardiograms
• Serial audiograms or brainstem auditory evoked response (critical for language development age) 1

Disease evaluations:

• Full evaluation at: end of induction, start of postconsolidation, end of therapy
• ¹²³I-MIBG scan halfway through postconsolidation 1

Adult-Specific Considerations

Adults with high-risk neuroblastoma have distinct biology and poorer outcomes compared to children (10-year OS only 19% for stage 4 disease). 2 The genetic profile differs, showing ATRX mutations (58%) and ALK mutations (42%) but typically no MYCN amplification. 2

Key principle: Apply the same general treatment framework as pediatric protocols, but expect the need for dose modifications and management of comorbidities. 1 Anti-GD2 immunotherapy is well-tolerated in adults with similar adverse events as children and shows 71.4% response rate in refractory disease. 2

Complete response after induction predicts superior survival - this should be the therapeutic goal. 2

Common Pitfalls

• Do not skip tandem transplant in favor of single transplant without specific contraindications - the survival benefit is significant
• Do not add interleukin-2 to immunotherapy regimen (outdated approach)
• Do not extend radiation fields beyond primary site and residual metastatic disease
• Do not assume adult patients cannot tolerate pediatric protocols - the same intensive approach should be attempted with appropriate monitoring