Background
Phase III RCT (COG ANBL0532). 652 patients with high-risk neuroblastoma. All patients received induction chemotherapy followed by surgical resection and local RT; randomized to single high-dose chemotherapy (HDCT) with PBSC rescue vs tandem HDCT (two sequential myeloablative courses with PBSC rescue). All received isotretinoin maintenance.
Interventions and follow up
Arm A: Single HDCT: carboplatin + etoposide + melphalan (CEM) × 1 course → PBSC rescue → local RT → isotretinoi
Arm B: Tandem HDCT: thiotepa + cyclophosphamide → PBSC rescue → CEM → PBSC rescue → local RT → isotretinoi
Primary endpoint: EFS
mFollow up: 3.8 years (interim analysis)
Arm B: Tandem HDCT: thiotepa + cyclophosphamide → PBSC rescue → CEM → PBSC rescue → local RT → isotretinoi
Primary endpoint: EFS
mFollow up: 3.8 years (interim analysis)
Results
3-yr EFS (tandem): 61.4% vs single 48.4%, P=.0052
3-yr OS (tandem): 74.0% vs single 69.1%, P=.19
RT component: Involved-field RT 21.6 Gy given post-HDCT in both arms; associated with improved local control
3-yr OS (tandem): 74.0% vs single 69.1%, P=.19
RT component: Involved-field RT 21.6 Gy given post-HDCT in both arms; associated with improved local control
Adverse events
Main adverse events: Tandem arm: higher rates of grade ≥3 mucositis (64% vs 38%), infection, organ toxicity. Second transplant-related mortality: 2.4% vs 0.7%. Late effects: hearing loss (cisplatin-based induction), growth failure, secondary malignancies.
Conclusions
Tandem HDCT significantly improved EFS versus single HDCT in high-risk neuroblastoma, without a significant OS benefit at this follow-up. Tandem consolidation became the standard of care for high-risk neuroblastoma at COG institutions.
Key Limitations
Key Limitations: OS benefit not significant at interim analysis. Significant increase in treatment-related toxicity with tandem approach. Long-term late effects of tandem HDCT not fully characterized. RT was administered post-HDCT with full 21.6 Gy dose in both arms — RT dose optimization not studied.
Clinical Context
ANBL0532 established tandem HDCT as standard consolidation for high-risk neuroblastoma in North America. Local RT 21.6 Gy to the primary site remains standard after HDCT. Anti-GD2 immunotherapy (dinutuximab) added to isotretinoin maintenance (COG ANBL0032) further improves outcomes.
References
References: Park JR et al, JCO 2019 (ANBL0532)