Treatment of Neuroblastoma
Risk-Stratified Treatment Framework
Treatment of neuroblastoma must be determined by risk classification integrating INRG stage, age, MYCN amplification status, histopathology, segmental chromosomal aberrations, and tumor ploidy—with MYCN amplification overriding all other factors to mandate high-risk treatment except for completely resected L1 tumors. 1, 2
The fundamental principle is that risk classification must occur before initiating any therapy, as this determines whether a child receives observation alone, moderate chemotherapy, or intensive multimodality treatment. 2
Low-Risk Disease (5-Year Survival >95%)
For low-risk INRG L1 tumors, perform surgical resection when it can be done safely with minimal morbidity. 1, 2
Specific Treatment Algorithms:
Infants <6 months with isolated adrenal masses: Observation without biopsy is appropriate if the mass is ≤3.1 cm (solid) or ≤5 cm (if ≥25% cystic). 1, 2, 3
Asymptomatic INRG MS disease with favorable biology: Observation is the preferred approach without immediate intervention. 1, 3
All other low-risk L1 tumors: Proceed directly to surgical resection as the sole treatment modality. 3
Critical Pitfall:
If incomplete resection reveals MYCN amplification on final pathology, immediately reassign the patient to high-risk protocol regardless of initial staging. 1, 4, 3 This represents one of the most important management decision points, as missing this reclassification leads to catastrophic undertreatment.
No chemotherapy or radiation is required for most low-risk patients. 3
Intermediate-Risk Disease (5-Year Survival 90-95%)
Administer 2-8 cycles of cyclophosphamide-based chemotherapy followed by surgical resection, with the number of cycles determined by age, stage, and biologic features. 1, 2, 3
Treatment Response Goals:
Localized tumors with favorable biology: Achieve ≥50% reduction in primary tumor volume before considering surgery. 1, 3
Localized tumors with unfavorable biology: Continue chemotherapy until achieving 90% reduction in primary tumor volume. 1, 3
If biologic features (SCA or histology) are unavailable: Treat as unfavorable biology to avoid undertreatment. 1
Surgical Timing and Approach:
Perform surgery only after achieving target tumor reduction with chemotherapy. 3 Preservation of vital structures and end-organ function is paramount—accept less than complete resection rather than causing permanent morbidity. 3
If chemotherapy results in <50% tumor size reduction, consider surgery if feasible; otherwise, administer additional chemotherapy with re-evaluation every 2 cycles. 3
No radiation is routinely indicated for intermediate-risk disease. 3
Special Consideration for Unstable Infants:
For infants with stage MS disease who are too clinically unstable to undergo biopsy safely, initiate chemotherapy first and obtain tissue diagnosis when the patient stabilizes. 1
High-Risk Disease (5-Year Survival <50%)
High-risk neuroblastoma requires intensive multimodality therapy including induction chemotherapy, surgical resection, myeloablative consolidation with autologous stem cell transplant, radiation therapy, immunotherapy with dinutuximab, and maintenance therapy. 2, 3
Automatic High-Risk Assignment Criteria:
- MYCN amplification (except completely resected L1 tumors) 1, 2, 4
- Age ≥18 months with stage M disease (regardless of other features) 4, 3
- Age 12-18 months with M or MS disease plus unfavorable histology, segmental chromosomal aberrations, or MYCN amplification 4
Immunotherapy Component:
Dinutuximab is FDA-approved in combination with GM-CSF, IL-2, and 13-cis-retinoic acid for pediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy. 5
Critical Monitoring Requirements:
- Serial cardiac function assessment due to cardiotoxicity risk 3
- Audiological monitoring (most patients develop ototoxicity from platinum-based chemotherapy, with 13% experiencing new or worsening hearing loss after eflornithine) 3
- Full disease evaluation at end of induction, start of post-consolidation, and end of therapy using revised INRC criteria and modified Curie score for MIBG imaging 2, 3
Emerging Targeted Therapies:
For tumors with ALK amplification or activating mutations, consider ALK inhibitors as targeted therapy. 2, 3 Next-generation sequencing should be performed to identify actionable mutations. 3
Sobering Reality:
Approximately 9% of high-risk patients progress despite intensive induction regimens. 4, 3 Survivors face significantly elevated risks of grade 3-5 chronic health conditions, second malignant neoplasms, and treatment-related organ dysfunction requiring lifelong monitoring. 2, 4, 3
Essential Pre-Treatment Molecular Testing
Before initiating any therapy, obtain the following molecular and pathologic assessments: 1, 2
- MYCN amplification status (strongest independent prognostic factor) 1, 4
- Segmental chromosomal aberrations (1p, 11q, 3p, 4p, 17q, 1q, 2p) 1, 4
- Tumor cell ploidy (DNA index) 1, 4
- ALK gene amplification/mutations 1, 2
- Histology classification per International Neuroblastoma Pathology Classification 1, 4
- Bilateral bone marrow aspirates and core biopsies (≥10% tumor infiltration distinguishes stage M from MS) 2
For imaging, 123I-MIBG scintigraphy is the primary functional imaging modality, with FDG-PET mandatory for MIBG-nonavid or suspected mixed-avidity disease. 2
Additional Management Considerations
Discuss fertility preservation before initiating chemotherapy when clinically feasible. 2, 3
Strongly encourage clinical trial participation for all patients, as ongoing trials continue to refine treatment strategies and identify novel therapeutic approaches. 3
A multidisciplinary team including diagnostic radiologists, nuclear medicine physicians, interventional radiologists, surgeons, anatomic pathologists, molecular pathologists, radiation oncologists, and pediatric oncologists should guide all treatment decisions. 1