Background
Phase III COG study (AREN0533). 585 patients with stage II–IV favorable histology Wilms tumor (FHWT). Risk-stratified treatment based on blastemal predominance and stage. All stage III–IV patients received flank/abdominal RT; stage II blastemal-predominant also escalated. Evaluated whether blastemal-predominant histology identifies patients requiring treatment intensification with doxorubicin-based regimen (DD-4A + cyclophosphamide/etoposide).
Interventions and follow up
Arm A: Standard-risk (non-blastemal FHWT stage II–III): Regimen DD-4A (vincristine + dactinomycin + doxorubicin) + RT per stage
Arm B: High-risk (blastemal-predominant or stage IV): Regimen M (vincristine + dactinomycin + doxorubicin + cyclophosphamide + etoposide) + RT
Primary endpoint: 4-year EFS
mFollow up: 4.0 year
Arm B: High-risk (blastemal-predominant or stage IV): Regimen M (vincristine + dactinomycin + doxorubicin + cyclophosphamide + etoposide) + RT
Primary endpoint: 4-year EFS
mFollow up: 4.0 year
Results
4-yr EFS (stage III, DD-4A): 85.7%
4-yr EFS (blastemal-predominant, Regimen M): 83.2% — substantially improved vs historical 65%
4-yr OS: 96.6% (stage II–III) vs 86.4% (stage IV)
RT adherence: Flank RT 10.8 Gy; whole abdomen RT 10.5 Gy (stage III diffuse spillage or rupture)
4-yr EFS (blastemal-predominant, Regimen M): 83.2% — substantially improved vs historical 65%
4-yr OS: 96.6% (stage II–III) vs 86.4% (stage IV)
RT adherence: Flank RT 10.8 Gy; whole abdomen RT 10.5 Gy (stage III diffuse spillage or rupture)
Adverse events
Main adverse events: Regimen M: significantly more myelosuppression, febrile neutropenia, and grade ≥3 GI toxicity vs DD-4A. RT late effects: scoliosis, ovarian failure (girls), renal dysfunction with whole abdominal RT. Doxorubicin cumulative cardiotoxicity risk.
Conclusions
Risk stratification based on blastemal predominance successfully identifies FHWT patients requiring treatment intensification. Escalation to Regimen M improved outcomes for blastemal-predominant tumors. Standard-risk stage II–III FHWT is cured with DD-4A + RT in >85% of cases.
Key Limitations
Key Limitations: Treatment allocation was not randomized — blastemal-predominant patients received intensification without a comparator arm. Central pathology review was essential but laborious. Molecular biomarkers (loss of heterozygosity 1p/16q) were studied but not used for further treatment escalation in this trial.
Clinical Context
AREN0533 established the current COG risk-stratification schema for FHWT. Blastemal predominance is now a standard pathologic assessment guiding treatment intensity. Flank RT 10.8 Gy (stage III) or whole abdominal RT 10.5 Gy (diffuse spillage) with DD-4A or Regimen M is current standard of care.
References