Background: FAWT represents tumors with circumscribed small areas of anaplastic nuclear changes confined to the kidney within an otherwise favorable histology WT. In National Wilms Tumor Study-5, patients with stage I FAWT treated with vincristine and dactinomycin (VA) without flank radiation had 4-year event-free survival (EFS) and overall survival (OS) of 67.5% and 88.9%, respectively. Patients with stage II-IV FAWT were treated with VA plus doxorubicin and radiation (DD4A). Of the 20 patients with stage II-III FAWT, 4 had a relapse and 3 died. The 4-year EFS and OS for stage IV FAWT/upfront nephrectomy were 61.4% and 71.6%, respectively. The COG AREN0321 study evaluated whether intensifying therapy for stage I and IV FAWT would improve survival of these patients. Methods: Tumor histology and stage were confirmed for all patients by real-time central pathology, surgery, and radiology review on protocol AREN03B2, the COG renal tumor classification, biology, and banking study. Patients then enrolled on AREN0321 with stage I-III FAWT received DD4A and those with stage IV FAWT received vincristine, doxorubicin, cyclophosphamide, carboplatin and etoposide with radiation (UH-1). We analyzed outcomes of patients with FAWT treated on AREN0321 and those enrolled only on AREN03B2 who received the same chemotherapy regimens. Results: A total of 46 patients (25 AREN0321 and 21 AREN03B2) were included in the analyses. Of the 25 AREN0321 patients, 17 (68%) had upfront nephrectomy and all 25 received radiation. Of the 5 AREN0321 patients with stage IV FAWT, 4 had metastasis to lung and 1 to lung and liver. Of the 21 AREN03B2 patients, 19 (90%) had upfront nephrectomy and 17 (81%) reported receiving radiation. The 2 AREN03B2 stage IV patients had lung only metastases. The 4-year EFS and OS are displayed in the table below. No events occurred in stage I-II AREN0321 patients nor in any AREN03B2 patients. Of 10 patients with stage III FAWT on AREN0321, 3 had a relapse. None of the 7 stage IV FAWT patients who received UH-1 had a relapse, but one patient died due to toxicity. Conclusions: Patients with stage I and II FAWT had outstanding survival when treated with DD4A and radiation. Intensification of therapy may be warranted for stage III FAWT and appears to have improved patient survival for stage IV FAWT but with increased risk of toxicity. Strategies to alleviate toxicity of UH-1 therapy have been incorporated into the ongoing COG trial for high-risk patients. Clinical trial information: NCT00335556.