What are the current treatment options and outcomes for pediatric neuroblastoma, including the newest treatments?

Outcomes and Treatment for Pediatric Neuroblastoma

Current Survival Outcomes by Risk Group

Five-year survival rates for pediatric neuroblastoma are excellent for low-risk disease (>95%), favorable for intermediate-risk disease (90-95%), but remain poor for high-risk disease (<50%), despite intensive multimodality therapy. 1, 2

The dramatic difference in outcomes reflects the biological heterogeneity of this disease:

• Low-risk patients achieve >95% 5-year survival with minimal intervention, often surgery alone or observation 1, 3
• Intermediate-risk patients maintain 90-95% 5-year survival with 2-8 cycles of chemotherapy 1, 3
• High-risk patients face <50% 5-year survival despite receiving the most intensive treatment regimens available 2

Population-based data from the United States confirms that 21% of all neuroblastoma patients die within 5 years, with mortality concentrated in the high-risk group 4. Patients with stage 4 disease, MYCN amplification, or unfavorable DNA ploidy have significantly worse survival 4.

Risk Stratification Framework

The COG 2021 risk classification system integrates six prognostic factors before treatment initiation: age at diagnosis, INRG stage, MYCN amplification status, histopathology, segmental chromosomal aberrations, and tumor ploidy. 2, 5

Critical risk assignment rules:

• MYCN amplification overrides nearly all other factors, automatically assigning high-risk status except for completely resected L1 tumors 2, 3
• All patients ≥18 months with stage M disease are high-risk regardless of any other features 2, 3
• Infants <6 months with small adrenal masses (≤3.1 cm if solid, ≤5 cm if ≥25% cystic) may be observed without biopsy 3, 6

Current Treatment Approaches

Low-Risk Disease Treatment

Surgical resection alone is the standard treatment for low-risk L1 tumors, with observation without biopsy appropriate for select neonates with small adrenal masses. 3

• Surgery should be performed when it can be done safely with minimal morbidity 1, 3
• For asymptomatic INRG MS disease with favorable biology, observation is preferred 1, 3
• No chemotherapy or radiation is required for most low-risk patients 3
• If incomplete resection reveals MYCN amplification, immediately reassign to high-risk protocol 3

Intermediate-Risk Disease Treatment

Intermediate-risk patients require 2-8 cycles of cyclophosphamide-based chemotherapy with response-adapted treatment goals: ≥50% tumor volume reduction for favorable biology tumors and 90% reduction for unfavorable biology tumors. 1, 3

Treatment algorithm:

• Administer chemotherapy until target tumor reduction is achieved 3
• Perform surgical resection after achieving target reduction, prioritizing preservation of vital structures over complete resection 3
• If <50% reduction occurs, consider surgery if feasible 3
• If surgery cannot be performed safely, give additional chemotherapy with re-evaluation every 2 cycles 3
• No radiation is routinely indicated 3

High-Risk Disease Treatment

High-risk neuroblastoma requires intensive four-phase multimodality therapy: induction chemotherapy, consolidation with surgery/high-dose chemotherapy/stem cell rescue/radiotherapy, post-consolidation immunotherapy with dinutuximab plus GM-CSF and IL-2, and maintenance with eflornithine. 3, 6

Phase 1: Induction

• Intensive multi-agent chemotherapy to achieve maximal tumor reduction 3, 7
• Approximately 9% of patients progress despite intensive induction 3

Phase 2: Consolidation

• Surgical resection of primary tumor with focus on preserving vital structures 3, 7
• Myeloablative high-dose chemotherapy with autologous stem cell rescue 3, 4, 7
• Consolidative radiotherapy to residual soft tissue disease 3, 4

Phase 3: Post-Consolidation Immunotherapy

Dinutuximab (anti-GD2 monoclonal antibody) in combination with GM-CSF, IL-2, and 13-cis-retinoic acid is FDA-approved for high-risk neuroblastoma patients who achieve at least partial response to first-line therapy. 8

• Dinutuximab binds to GD2 glycolipid expressed on neuroblastoma cells 8
• Given for up to 5 cycles in alternating combination with GM-CSF and IL-2 8
• This regimen demonstrated improved event-free survival and overall survival in randomized trials 8

Phase 4: Maintenance

• Eflornithine as continuation therapy after completing anti-GD2 immunotherapy 3
• 13-cis-retinoic acid (isotretinoin) for differentiation therapy 4, 7

Newest Treatment Developments

The most significant recent advance is the incorporation of anti-GD2 immunotherapy (dinutuximab) into standard high-risk treatment, which has improved survival outcomes. 8, 7

Emerging targeted therapies under investigation:

• ALK inhibitors for tumors with ALK amplification or activating mutations 1, 9
• Next-generation sequencing now enables identification of actionable mutations to guide targeted therapy selection 1
• Novel agents are being tested in phase I/II trials with plans for incorporation into mainstream protocols if successful 9

Critical Monitoring Requirements

High-risk patients require intensive organ function monitoring due to treatment toxicity: serial cardiac function assessment with ECG/echocardiography, audiological monitoring with audiograms or brainstem auditory evoked response, and detailed renal function evaluation including nuclear medicine GFR measurements before consolidation. 1, 6

• Most high-risk patients experience ototoxicity from platinum-based chemotherapy 1
• 13% of patients develop new or worsening hearing loss after eflornithine initiation 1
• Hearing loss is particularly critical as most patients are at critical ages for language development 1
• Fertility preservation should be discussed before chemotherapy initiation when possible 1

Response Assessment

Disease response evaluation uses revised INRC criteria (2017) based on RECIST criteria for anatomic imaging and semiquantitative scoring (modified Curie score) for 123I-MIBG functional imaging. 1, 6

• 123I-MIBG scintigraphy is the primary imaging modality, with uptake in up to 90% of neuroblastomas 2, 6
• FDG-PET imaging is mandatory for MIBG-nonavid or mixed-avidity disease 2, 6
• Urinary catecholamines (HVA/VMA) are no longer used for response assessment due to lack of standardization 1

Long-Term Survivorship Concerns

Survivors of high-risk neuroblastoma face significantly elevated risks of late morbidity and mortality, including grade 3-5 chronic health conditions, second malignant neoplasms, and treatment-related organ dysfunction. 1

• All-cause mortality is higher across all risk groups compared to general population 1
• High-risk survivors require lifelong surveillance per COG Survivorship Guidelines for thyroid, cardiac, pulmonary, renal, bone, reproductive health, and second malignancies 1
• Intermediate-risk patients have lower but still elevated risks due to lower cumulative chemotherapy exposures 1

Clinical Trial Enrollment

76% of neuroblastoma patients in the United States are enrolled on risk-based clinical trials, reflecting the strong cooperative group infrastructure for this disease. 4

The NCCN guidelines strongly encourage clinical trial participation for all patients, as trials continue to refine treatment strategies and identify new therapeutic approaches 1.