This phase III trial studies using risk factors in determining treatment for children with favorable tissue (histology) Wilms tumors (FHWT). Wilms Tumor is the most common type of kidney cancer in children, and FHWT is the most common subtype. Previous large clinical trials have established treatment plans that are likely to cure most children with FHWT, however some children still have their cancer come back (called relapse) and not all survive. Previous research has identified features of FHWT that are associated with higher or lower risks of relapse. The term "risk" refers to the chance of the cancer coming back after treatment. Using results of tumor histology tests, biology tests, and response to therapy may be able to improve treatment for children with FHWT.

PRIMARY OBJECTIVES:

I. To maintain event-free survival (EFS) for Stage I favorable histology Wilms tumor (FHWT) patients without adverse biology who are also (1) 2 to < 4 years of age, OR (2) age < 2 years with tumor weight of 550 grams or more, OR (3) age 4+ years with epithelial histology subtype while reducing post-nephrectomy therapy from vincristine, actinomycin (EE-4A) to Nephrectomy Only. (Stage I Nephrectomy Only Stratum 2) II. To improve EFS for Stage I FHWT patients with age < 2 years AND nephrectomy weight < 550g AND whose tumors have adverse biology by treating with EE-4A instead of Nephrectomy Only. (Stage I EE-4A Stratum 3) III. To evaluate whether addition of vincristine and irinotecan to standard EE-4A (novel vincristine, actinomycin, irinotecan [Regimen VIVA]) is non-inferior to vincristine, actinomycin, doxorubicin (DD-4A) in terms of EFS among Stage II FHWT patients whose tumors demonstrate adverse biology. (Stage II: VIVA versus [vs] DD-4A Randomization) IV. To evaluate whether omission of doxorubicin (EE-4A) is non-inferior to historical DD-4A in Stage III FHWT patients without adverse biology or post-therapy blastemal predominance. (Stage III: EE-4A) V. To demonstrate the non-inferiority of vincristine, actinomycin, doxorubicin, cyclophosphamide, etoposide and irinotecan (Regimen MVI) to vincristine, dactinomycin, doxorubicin, cyclophosphamide and etoposide (Regimen M) in the treatment of Stage III FHWT patients whose tumors exhibit adverse biology (post-chemotherapy blastemal predominance excluded). (Stage III: Regimen MVI vs Regimen M Randomization) VI. To demonstrate the non-inferiority of Regimen MVI to Regimen M in the treatment of Stage IV FHWT patients with adverse biology, slow incomplete lung response (SIR), or extrapulmonary metastases (EPM) (post-therapy blastemal predominance excluded). (Stage IV: Regimen MVI vs Regimen M Randomization) VII. To demonstrate the superiority of vincristine, doxorubicin, cyclophosphamide, etoposide, carboplatin and irinotecan (Regimen UH-3) vs historical DD-4A or Regimen M in treatment of Stage III or IV FHWT patients with blastemal predominance at delayed nephrectomy. (Stage III-IV: UH-3 [Blastemal Predominance])

SECONDARY OBJECTIVES:

I. To describe outcomes for Stage I FHWT patients without adverse biology who are either less than 4 years of age OR 4+ years of age with epithelial subtype who are treated with Nephrectomy Only and assess consistency with a matched historical control from the prior Children's Oncology Group (COG) therapeutic era. (Stage I: Nephrectomy Only) II. To describe outcomes for Stage I FHWT patients with adverse biology OR age > 4 and not epithelial subtype who are treated with post-nephrectomy EE-4A and assess consistency with a matched historical control from the prior COG therapeutic era. (Stage I: EE-4A) III. To describe overall survival in the cohort of modified very low risk (mVLR) patients who relapse following treatment with nephrectomy only and are assigned at relapse to DD-4A (if presumed or confirmed favorable histology Wilms tumor at relapse) or UH-3 (if evidence of anaplasia at relapse). (Stage I: Nephrectomy Only Relapse) IV. To describe outcomes for Stage II FHWT patients without adverse biology who are treated with post-nephrectomy EE-4A and assess consistency with a matched historical control from the prior COG therapeutic era. (Stage II: EE-4A) V. To compare outcomes of Stage II FHWT patients whose tumors are negative for combined loss of heterozygosity (LOH) but positive for 1q gain who are randomized to VIVA vs DD-4A on AREN2231 against historically matched patients treated with EE-4A during the prior COG therapeutic era. (Stage II VIVA vs DD-4A Stratum 1) VI. To compare outcomes of Stage II FHWT patients whose tumors are positive for combined LOH 1p AND 16q and who are randomized to VIVA vs DD-4A on AREN2231 against historically matched patients treated with DD-4A during the prior COG therapeutic era. (Stage II VIVA vs DD-4A Stratum 2) VII. To compare outcomes of Stage III FHWT patients whose tumors have adverse biology other than combined LOH and who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with DD-4A during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage III Regimen MVI vs Regimen M Stratum 1) VIII. To compare outcomes of Stage III FHWT patients whose tumors have combined LOH and who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with Regimen M during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage III Regimen MVI vs Regimen M Stratum 2) IX. To describe outcomes for Stage IV FHWT patients with rapid complete response of lung only metastases and no adverse biology who are treated with DD-4A on AREN2231 and assess consistency with a matched historical control from the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV: DD-4A) X. To compare outcomes of Stage IV lung only patients with either combined LOH 1p AND 16q or SIR who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with Regimen M during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV Regimen MVI vs Regimen M Stratum 1) XI. To compare outcomes of Stage IV lung only rapid complete response (RCR) patients without combined LOH 1p AND 16q who are positive for other adverse biological factors and who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with DD-4A during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV Regimen MVI vs Regimen M Stratum 2) XII. To compare outcomes of Stage IV patients with extrapulmonary metastases (EPM) who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with Regimen M during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV Regimen MVI vs Regimen M Stratum 3) XIII. To report a pooled comparison of Regimen MVI vs Regimen M in Stage III or Stage IV randomized patients. (Stage III-IV Regimen MVI vs Regimen M) XIV. To compare outcomes of Stage III or IV FHWT patients with blastemal predominance at delayed nephrectomy who are treated with Regimen UH-3 on AREN2231 vs a historically matched cohort that received DD-4A in the prior COG therapeutic era. (Stage III-IV UH-3 Stratum 1) XV. To compare outcomes of Stage III or IV FHWT patients with blastemal predominance at delayed nephrectomy who are treated with Regimen UH-3 on AREN2231 vs a historically matched cohort that received Regimen M in the prior COG therapeutic era. (Stage III-IV UH-3 Stratum 2) XVI. To describe outcomes of Stage III or IV FHWT patients with delayed nephrectomy occurring after the start of Cycles 3 or 4 (super delayed) who are assigned to Regimen M or continued DD4A. (Stage III-IV Super Delayed Nephrectomy)

EXPLORATORY OBJECTIVES:

I. To determine the impact of imaging schedule and modality (chest x-ray [CXR], ultrasound [US], versus computed tomography/magnetic resonance imaging [CT/MRI], versus clinical symptoms) on relapse, timing of detection of relapse, burden of disease at relapse (as assessed by retrospective central imaging review), as well as impact on survival.

II. To analyze the impact of radiologically determined pulmonary tumor burden on outcomes.

III. To assess whether imaging modality (ultrasound, CT, MRI with or without hepatocyte specific contrast agent) at diagnosis is associated with detection of increased number of liver metastases, and whether modality choice impacts surgery and/or radiation planning for liver metastases.

IV. To accurately describe the responses of extrapulmonary metastases to the various therapeutic modalities (chemotherapy, radiation therapy, and surgery) through central review of institutional imaging at various stages of treatment, and to correlate institutionally interpreted radiologic response interpretations with central review.

V. To describe the association of the number of anatomically relevant and pathologically confirmed lymph nodes sampled and percent of positive lymph nodes (LNs) on EFS and overall survival (OS).

VI. To document the surgical and/or medical rationale and approach for biopsy (including type of biopsy, number of biopsies, and site of biopsy) for all patients who are treated with the approach of initial biopsy and delayed nephrectomy.

VII. To describe sites of recurrence for patients with liver metastases according to the surgery and/or radiation therapy administered for residual liver lesions at Week 6 and 12.

VIII. To increase the number of patients eligible to avoid lung radiation therapy (RT) by encouraging resection of residual pulmonary nodules for patients defined as Stage IV FHWT with standard biology and who have 1-3 residual pulmonary nodules on imaging after Cycle 2, by omitting lung RT for those who are found to have no viable tumor in resected nodules.

IX. To describe whether residual lung lesions at end of therapy are associated with relapse.

X. To improve the reliability of data derived from central surgical review through the implementation of a standardized operative note.

XI. To describe the treatment, perioperative morbidity and outcome of patients noted to have inferior vena cava (IVC) tumor thrombus at time of diagnosis, including surgical approach, pathology findings and specific radiation therapy received.

XII. To determine the feasibility of employing intensity modulated radiation therapy (IMRT) and proton therapy with central quality assurance (QA) monitoring within the prescribed time frame.

XIII. To determine the lung tumor and liver tumor control rate using IMRT and/or proton therapy and compare it to standard 3-dimensional radiotherapy in the current study and the AREN0533 study.

XIV. To determine the flank and abdominal tumor control rates in children with Stage IV FHWT who received abdominal radiotherapy after 2 cycles of chemotherapy in this study (delayed abdominal radiation) and compare it to AREN0533 study where abdominal radiotherapy was performed within 2 weeks of nephrectomy (upfront abdominal radiation).

XV. To compare abdominal relapse according to protocol-recommended radiotherapy fields (flank vs. whole abdominal) in the current study and compare it to the abdominal relapse according to radiotherapy fields (flank vs. whole abdominal) in the AREN0532 and AREN0533 studies.

XVI. To determine the impact of radiotherapy on local and distant control rates for EPM sites and compare them to EPM sites not receiving radiation.

XVII. To describe the rate and severity of recurrent hepatotoxicity in patients who undergo re-introduction of chemotherapy after experiencing hepatopathy.

XVIII. To collect serial blood and urine samples to bank for future research studies.

OUTLINE:

STAGE I FHWT: Patients will have already undergone nephrectomy and lymph node sampling prior to trial enrollment. Patients < 4 years old at diagnosis or with epithelial subtype FHWT of any age, undergo observation until tumor biomarker testing returns. Patients with adverse biology are assigned to Arm I. Patients with standard biology are assigned to Arm II and undergo observation post-nephrectomy until disease relapse. At the time of disease relapse, patients with favorable histology are assigned to Arm III, and patients with unfavorable (anaplastic) histology are assigned to Arm IV. Patients ≥ 4 years of age at diagnosis without epithelial FHWT are assigned to Arm I regardless of biology results.

• ARM I: Patients receive regimen EE-4A: Dactinomycin intravenously (IV) over 1-5 or 10-15 minutes on day 1 of cycles 1-7 and vincristine IV on days 1, 8, & 15 of cycles 1-3 and day 1 of cycles 4-7. Treatment repeats every 21 days for 7 cycles in the absence of disease progression or unacceptable toxicity.
• ARM II: Patients undergo observation without chemotherapy on study with ultrasounds and x-rays.
• ARM III: Patients receive regimen DD-4A: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 1, 3, 5, 7, & 9, vincristine IV on days 1, 8, & 15 of cycles 1-3 and day 1 of cycles 4-9, doxorubicin IV over 3-15 minutes on day 1 of cycles 2, 4, 6, & 8. Treatment repeats every 21 days for 9 cycles in the absence of disease progression or unacceptable toxicity.
• ARM IV: Patients receive regimen UH-3: Vincristine IV on days 1, 8, & 15 of cycles 1, 5, 7, 10, & 13, and days 1 & 8 of cycles 3, 4, 8, & 11, doxorubicin IV 3-15 minutes on day 1 of cycles 1, 5, 7, 10, & 13, cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 5, 7, 10, & 13, and days 1-4 of cycles 2, 6, 9, 12, & 14, carboplatin IV over 15-60 minutes on day 1 of cycles 2, 6, 9, 12, and 14, etoposide IV over 60-120 minutes on days 1-4 of cycles 2, 6, 9, 12, & 14, and irinotecan IV over 90 minutes on days 1-5 of cycles 3, 4, 8, & 11. Treatment repeats every 21 days for 14 cycles in the absence of disease progression or unacceptable toxicity.

STAGE II FHWT: Patients receive one cycle of regimen EE-4A as in STAGE I FHWT Arm I. Patients with standard biology are assigned to Arm I below. Patients with adverse biology are randomized to Arm II or Arm III below.

• ARM I: Patients receive cycles 2-7 of regimen EE-4A as in STAGE I FHWT Arm I.
• ARM II: Patients receive cycles 2-9 of regimen VIVA: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 3, 5, 7, & 9, vincristine IV on days 1, 8, & 15 of cycles 2-3 and day 1 of cycles 4-9, irinotecan IV over 90 minutes daily on days 1-5 of cycles 2, 4, 6, & 8. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
• ARM III: Patients receive cycles 2-9 of regimen DD-4A: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 3, 5, 7, and 9, vincristine IV on days 1, 8, and 15 of cycles 2-3 and day 1 of cycles 4-9, and doxorubicin IV over 3-15 minutes on day 1 of cycles 2, 4, 6, & 8. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

STAGE III FHWT: Patients able to undergo an upfront nephrectomy receive cycle 1 treatment of regimen DD-4A: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycle 1, vincristine IV on days 1, 8, & 15 of cycle 1. Patients with standard biology are assigned to Arm I below. Patients with adverse biology are assigned to Arm II below.

• ARM I: Patients receive cycles 2-7 of regimen EE-4A as in STAGE I FHWT Arm I.

• ARM II: Patients receive cycle 2 treatment of regimen DD-4A as in STAGE II FHWT Arm III above. They are then randomized to Arm IIA or Arm IIB below.

  • ARM IIA: Patients receive regimen MVI: Vincristine IV on days 1, 8, & 15 of cycle 3, days 8 & 15 of cycle 4, and day 1 of cycles 5 & 7-13, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 3, 7, 9, 11, & 13, doxorubicin IV over 3-15 minutes on day 1 of cycles 3, 7, 9, 11, & 13, cyclophosphamide IV over 15-30 minutes daily on days 1-5 of cycles 4 and 6, irinotecan IV over 90 minutes daily on days 1-5 of cycles 5, 8, 10 & 12, and etoposide IV over 60-120 minutes daily on days 1-5 of cycles 4 and 6. Treatment repeats every 21 days for 11 cycles in the absence of disease progression or unacceptable toxicity.
  • ARM IIB: Patients receive regimen M: Cyclophosphamide IV over 15-30 minutes daily on days 1-5 of cycles 3, 4, 7, & 9, etoposide IV over 60-120 minutes daily on days 1-5 of cycles 3, 4, 7, & 9, vincristine IV on days 8 & 15 of cycles 3 & 4 and day 1 of cycles 5, 6, 8, 10, & 11, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 5, 6, 8, 10, & 11, and doxorubicin IV over 3-15 minutes of cycles 5, 6, 8, 10, & 11.

STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY): Patients receive cycles 1-2 of regimen DD-4A: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycle 1, vincristine IV on days 1, 8, and 15 of cycles 1-2, and doxorubicin IV over 3-15 minutes on day 1 of cycle 2. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

• PATIENTS ABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology and low or intermediate risk histology are assigned to Arm I below. Patients with high risk histology are assigned to Arm II below. Patients with adverse biology and low or intermediate risk histology are randomized to Arm III or Arm IV below.

• PATIENTS UNABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology are assigned to Arm V below. Patients with adverse biology are randomized to Arm VI or Arm VII below.

• ARM I: Patients receive cycles 3-7 of regimen EE-4A as in STAGE I FHWT Arm I above.

• ARM II: Patients receive regimen UH-3 as in STAGE I FHWT Arm IV above: Vincristine IV on days 1, 8, & 15 of cycles 1, 5, 7, 10, & 13, and days 1 & 8 of cycles 3, 4, 8, & 11, doxorubicin IV 3-15 minutes on day 1 of cycles 1, 5, 7, 10, & 13, cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 5, 7, 10, & 13, and days 1-4 of cycles 2, 6, 9, 12, & 14, carboplatin IV over 15-60 minutes on day 1 of cycles 2, 6, 9, 12, and 14, etoposide IV over 60-120 minutes on days 1-4 of cycles 2, 6, 9, 12, & 14, and irinotecan IV over 90 minutes on days 1-5 of cycles 3, 4, 8, & 11. Treatment repeats every 21 days for 14 cycles in the absence of disease progression or unacceptable toxicity.

• ARM III: Patients receive regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM IV: Patients receive regimen M as in STAGE III FHWT Arm IIB above.

• ARM V: Patients receive cycles 3-4 of regimen DD-4A as in STAGE II FHWT Arm III above. They then undergo delayed nephrectomy after cycle 3 or 4. Patients with low or intermediate risk histology who still have standard biology are then assigned to Arm VA. Patients with low or intermediate risk histology with new adverse biology (positive lymph nodes, and LOH of 1p or 16q from original biopsy) are then assigned to Arm VB. Patients with high risk histology are assigned to Arm VIII below.

  • ARM VA: Patients receive cycles 5-9 (or 4-9 if nephrectomy occurred after cycle 3) of regimen DD-4A as in STAGE II FHWT Arm III above.
  • ARM VB: Patients receive cycles 5-9 (or 4-9 if nephrectomy occurred after cycle 3) of regimen M as in STAGE III FHWT Arm IIB above.

• ARM VI: Patients receive cycles 3-4 of regimen MVI as in STAGE III FHWT Arm IIA above. Patients with high risk histology after delayed nephrectomy after cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy after cycle 3 or 4 are assigned to Arm IX.

• ARM VII: Patients receive cycles 3-4 of regimen M as in STAGE III FHWT Arm IIB above. Patients with high risk histology after delayed nephrectomy after cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy after cycle 3 or 4 are assigned to Arm X.

• ARM VIII: Patients receive regimen UH-3 as in STAGE I FHWT Arm IV above.

• ARM IX: Patients receive cycles 5-13 (or 4-13 if nephrectomy occurred after cycle 3) of regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM X: Patients receive cycles 5-11 (or 4-11 if nephrectomy occurred after cycle 3) of regimen M as in STAGE III FHWT Arm IIB above.

STAGE IV FHWT LUNG METASTASES (UPFRONT NEPHRECTOMY): Patients receive cycles 1-2 of regimen DD-4A as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) above. Patients with standard biology and rapid complete lung response (RCR) are assigned to Arm I below. Patients with standard biology and slow incomplete lung response (SIR), or adverse biology (with either RCR or SIR) are randomized to Arm II or Arm III below.

• ARM I: Patients receive cycles 3-9 of regimen DD-4A as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arms V and VA above.
• ARM II: Patients receive regimen MVI as in STAGE III FHWT Arm IIA above.
• ARM III: Patients receive regimen M as in STAGE III FHWT Arm IIB above.

STAGE IV FHWT LUNG METASTASES (UPFRONT BIOPSY/DELAYED NEPHRECTOMY): Patients receive cycles 1-2 of regimen DD-4A as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) above.

• PATIENTS ABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology, low or intermediate risk histology, and RCR are assigned to Arm I below. Patients with high risk histology are assigned to Arm II below. Patients with adverse biology OR SIR and low or intermediate risk histology are randomized to Arm III or Arm IV below.

• PATIENTS UNABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology and RCR are assigned to Arm V below. Patients with standard biology and SIR OR adverse biology and either SIR or RCR are randomized to Arm VI or Arm VII below.

• ARM I: Patients receive cycles 3-9 of regimen DD-4A as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arms V and VA above.

• ARM II: Patients receive regimen UH-3 as in STAGE I FHWT Arm IV above.

• ARM III: Patients receive regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM IV: Patients receive regimen M as in STAGE III FHWT Arm IIB above.

• ARM V: Patients continue with regimen DD4A for up to 4 cycles, until time of delayed nephrectomy after cycle 3 or 4 of regimen DD-4A as in STAGE II FHWT Arm II above. They then undergo delayed nephrectomy after cycle 3 or 4. Patients with low or intermediate risk histology still with standard biology are then assigned to Arm VA. Patients with low or intermediate risk histology and new adverse biology (positive lymph nodes, and LOH of 1p or 16q from original biopsy) are then assigned to Arm VB. Patients with high risk histology are assigned to Arm VIII below.

  • ARM VA: Patients receive cycles 5-9 (or 4-9 if nephrectomy occurred after cycle 3) of regimen DD-4A as in STAGE II FHWT Arm II above.
  • ARM VB: Patients receive regimen M as in STAGE III FHWT Arm IIB above.

• ARM VI: Patients continue with regimen MVI for up to 4 cycles, until time of delayed nephrectomy after cycles 3 or 4 of regimen MVI as in STAGE III FHWT Arm IIA above. Patients with high risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm IX.

• ARM VII: Patients continue with regimen M for up to 4 cycles, until time of delayed nephrectomy after cycles 3 or 4 of regimen M as in STAGE III FHWT Arm IIB above. Patients with high risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm X.

• ARM VIII: Patients receive regimen UH-3 as in STAGE I FHWT Arm IV above.

• ARM IX: Patients continue cycles 5-13 (or 4-13 if nephrectomy occurred after cycle 3) of regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM X: Patients continue cycles 5-11 (or 4-11 if nephrectomy occurred after cycle 3) of regimen M as in STAGE III FHWT Arm IIB above. NOTE: Patients who receive 4 cycles of initial treatment per regimen DD-4A omit cycle 11.

STAGE IV FHWT EXTRAPULMONARY METASTASES: Patients receive 2 cycles of regimen DD-4A as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) above.

PATIENTS ABLE TO UNDERGO UPFRONT NEPHRECTOMY: Patients are randomized to Arm I or II below.

PATIENTS ABLE TO UNDERGO DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with low or intermediate risk histology are randomized to Arm III or IV.

PATIENTS ABLE TO UNDERGO DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with high risk histology are assigned to Arm V.

PATIENTS UNABLE TO UNDERGO DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients are randomized to Arm VI or VII.

• ARM I: Patients receive regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM II: Patients receive regimen M as in STAGE III FHWT Arm IIB above.

• ARM III: Patients receive regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM IV: Patients receive regimen M as in STAGE III FHWT Arm IIB above.

• ARM V: Patients receive regimen UH-3 as in STAGE I FHWT Arm IV above.

• ARM VI: Patients receive cycles 3-4 of regimen MVI as in STAGE III FHWT Arm IIA above. Patients undergoing nephrectomy after cycles 3 or 4 and with low or intermediate risk histology are assigned to Arm IX below. Patients undergoing nephrectomy after cycles 3 or 4 and with high risk histology are assigned to Arm VIII below

• ARM VII: Patients receive cycles 3-4 of regimen M as in STAGE III FHWT Arm IIB above. Patients undergoing nephrectomy after cycles 3 or 4 and with low or intermediate risk histology are assigned to Arm X below. Patients undergoing nephrectomy after cycles 3 or 4 and with high risk histology are assigned to Arm VIII below.

• ARM VIII: Patients receive regimen UH-3 as in STAGE I FHWT Arm IV above.

• ARM IX: Patients receive cycles 5-13 (or 4-13 if nephrectomy occurred after cycle 3) of regimen MVI as in STAGE III FHWT Arm IIA above.

• ARM X: Patients receive cycles 5-11 (or 4-11 if nephrectomy occurred after cycle 3) of regimen M as in STAGE III FHWT Arm IIB above.

  • NOTE: Patients receiving regimens EE-4A, DD-4A, VIVA, M, MVI & UH3 also undergo computed tomography (CT), CT or magnetic resonance imaging (MRI), ultrasound, and X-ray imaging throughout the trial. Patients with metastatic sites outside the chest/abdomen/pelvis documented during therapy may also undergo bone scan and/or positron emission tomography (PET).

After completion of study treatment, patients are followed for 10 years.

Inclusion Criteria:

• Patients must be enrolled on APEC14B1 and consent to Part A - Eligibility Screening prior to enrollment on AREN2231.

• Patients must be < 30 years old at enrollment.

• Patients with newly diagnosed Stage I-IV Favorable Histology Wilms Tumor confirmed by central review and with a qualifying Initial Stratum Assignment on APEC14B1.

• Patients must receive a qualifying Initial Stratum Assignment on APEC14B1-REN by Day 14 post-diagnostic procedure (nephrectomy or biopsy), where that procedure is Day 0.

  • Patients must enroll on AREN2231 by Day 14.
  • Exceptions: If patient reaches Day 14 (post initial diagnostic nephrectomy or biopsy) without receiving an Initial Stratum Assignment on APEC14B1-REN, patient will not be eligible for enrollment on AREN2231 unless all required materials (reports and Case Report Forms and specimens) for an Initial Stratum Assignment arrived by Day 7, but an Initial Stratum Assignment was not completed by Day 14. In these circumstances, after obtaining appropriate protocol consent, the patient may proceed with treatment according to local institutional staging and enroll within 5 calendar days of notification of the central Initial Stratum Assignment being issued, only if the AREN2231 Initial Stratum Assignment is in agreement with any treatment already initiated. If the Initial Stratum Assignment is not in agreement with the local institution's assessment then the patient will be ineligible for AREN2231.

• All sites must have sent or plan to send diagnostic tumor sample for molecular testing through a Clinical Laboratory Improvement Act (CLIA)-certified (or equivalent if outside of the United States [US]) laboratory that can detect Loss of Heterozygosity (LOH) of chromosome 1p AND 16q, and gain of chromosome 1q. Patients potentially eligible for mVLR must also have LOH of chromosome 11p15 included.

  • Note: Patients are eligible for enrollment prior to obtaining these molecular testing results, and it is strongly recommended that patients are enrolled before these results are available. However, molecular results must be returned and uploaded to APEC14B1-REN for integration into risk stratification by the required timepoints (specific timelines vary by treatment arm). Patients who do not have molecular results available by the arm-specific timepoints may be taken off protocol therapy.

• Patients who have an upfront nephrectomy must have at least one lymph node sampled and confirmed as a lymph node by central pathology review to be eligible.

  • Note: Lymph node sampling will also be required at delayed nephrectomy. Patients who do not have a lymph node sampled and confirmed as a lymph node by central pathology review at delayed nephrectomy will be taken off protocol therapy.

• Karnofsky performance status must be ≥ 50 for patients > 16 years of age and the Lansky performance status must be ≥ 50 for patients ≤ 16 years of age.

• ONLY TO PATIENTS WHO WILL RECEIVE CHEMOTHERAPY: Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) OR direct bilirubin ≤ 3X ULN for subjects with total bilirubin levels > 1.5 ULN (within 7 days prior to enrollment).

• ONLY TO PATIENTS WHO WILL RECEIVE CHEMOTHERAPY: Aspartate aminotransferase (AST/serum glutamate oxaloacetic transaminase [SGOT]) OR alanine transaminase (ALT/serum glutamic pyruvate transaminase [SGPT]) ≤ 3X ULN OR ≤ 5 X ULN for patients with liver metastases (within 7 days prior to enrollment).

• ONLY TO PATIENTS WHO WILL RECEIVE CHEMOTHERAPY: Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% (within 7 days prior to enrollment)

  • Note: This criteria only applies to patients centrally classified as Stage IV. Stage II and III patients subsequently assigned to a doxorubicin arm will be off protocol therapy if they do not meet this criteria at time of cardiac function assessment.

• Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

• All patients and/or their parents or legal guardians must sign a written informed consent.

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Exclusion Criteria:

• Patient with a diagnosis of Stage V Bilateral Wilms Tumor.

• Patients who in the opinion of the investigator are not able to comply with the study procedures are not eligible.

• Patients with any uncontrolled, intercurrent illness including but not limited to symptomatic congestive heart failure.

• Patients with Stage I FHWT with a known or suspected Wilms Tumor predisposition syndrome or condition (contralateral nephrogenic rests and/or unilateral multicentric tumors) are excluded from treatment on the mVLR (Nephrectomy Only) arm.

  • Notes:

    • In the context of the renal tumor protocols, multicentric tumors and multifocal tumors are equivalent terms, and refer to the occurrence of two or more tumors arising within one kidney.

    • Exclusion from the Nephrectomy Only arm applies to two groups of patients:

      • Patients < 4 years with Stage I FHWT other than epithelial subtype AND
      • Stage I patients of any age with Epithelial WT

    • For the purpose of exclusion from the Nephrectomy Only Arm, known or suspected WT predisposition syndromes or conditions are defined as follows:

      • WT Predisposition Syndromes: Beckwith Wiedemann Spectrum, Denys Drash, Trisomy 18, Idiopathic Hemihypertrophy/Isolated Lateralized Overgrowth, WAGR, Simpson-Golabi-Behmel, Bohring-Opitz, or other conditions considered by treating physician to predispose to WT.

      • WT Predisposing Conditions:

        • A unilateral WT and (radiologic or pathologic) determination of contralateral nephrogenic rest(s) AND/OR
        • Unilateral multicentric WT

• Patients treated with partial nephrectomy at initial diagnosis are excluded from mVLR (Nephrectomy Only) arm.

• Patients with lung metastases as the only metastatic site who already had complete resection of all radiologically evident lung nodules, and have at least one nodule confirmed pathologically as tumor.

  • Please note: Those with lung metastases as the only metastatic site who have complete resection of all radiologically evident lung nodules after enrollment but prior to the lung imaging following Cycle 2 of DD-4A will be inevaluable for lung assessment and subsequent stratum assignment and will, therefore, come off protocol therapy.

• Patients with known Charcot-Marie-Tooth syndrome.

• Patients who have had prior tumor-directed chemotherapy or radiotherapy for the current diagnosis except for therapy delivered for an emergent issue, as medically indicated.

• Patients who will potentially require doxorubicin on this study and have previously received doxorubicin for another diagnosis.

• Patients receiving concurrent chemotherapy for a different diagnosis.

• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.

• Lactating females who plan to breastfeed their infants.

• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.