OBJECTIVES:

Primary

- Determine the 4-year event-free survival (EFS) of patients with stage IV favorable
histology (FH) Wilms tumor with pulmonary metastases only who have complete resolution
of pulmonary lesions without whole lung irradiation treated with DD4A chemotherapy
comprising vincristine, dactinomycin, and doxorubicin hydrochloride.

- Determine the 4-year EFS of these patients who do not have resolution of pulmonary
metastases by week 6 treated with the addition of cyclophosphamide and etoposide to a
modified-regimen DD4A (regimen M).

- Determine the 4-year EFS of patients with stage III or IV FH Wilms tumor with loss of
heterozygosity for chromosomes 1p and 16q treated with regimen M.

Secondary

- Correlate the burden of pulmonary metastatic disease with outcome in patients with
stage IV FH Wilms tumor.

OUTLINE: This is a multicenter study.

- Regimen DD4A (weeks 1-6): Patients receive dactinomycin IV over 1-5 minutes once in
week 1; vincristine IV once in weeks 1-6; and doxorubicin hydrochloride IV over 15
minutes once in week 4 in the absence of disease progression or unacceptable toxicity.
Patients with both pulmonary and extra-pulmonary metastases at diagnosis undergo
radiotherapy once daily beginning in week 1 and continuing for 5-14 days.

After completion of DD4A chemotherapy (week 6), patients undergo evaluation. Patients with
stage IV disease and pulmonary metastases only with no loss of heterozygosity (LOH) who are
rapid complete responders (RCR) (i.e., pulmonary metastases disappear) proceed to regimen
DD4A (weeks 7-25).

All other patients (i.e., patients with stage III or IV disease and LOH of both 1p and 16q;
stage IV disease with pulmonary metastases only who are slow incomplete responders [SIR]
[i.e., pulmonary metastases do not disappear]; or stage IV disease with nonpulmonary
metastases or with nonpulmonary metastases in combination with pulmonary metastases) proceed
to regimen M (weeks 7-31).

Patients with initially unresectable or incompletely resected tumors are reevaluated at week
6, and if resectable, undergo surgery and then proceed to either regimen DD4A or regimen M
as described above.

- Regimen DD4A (weeks 7-25): Patients receive dactinomycin IV over 1-5 minutes once in
weeks 7, 13, 19, and 25; vincristine IV once in weeks 7-10, 13, 16, 19, 22, and 25; and
doxorubicin hydrochloride IV over 15 minutes once in weeks 10, 16, and 22 in the
absence of disease progression or unacceptable toxicity.

- Regimen M (weeks 7-31): Patients receive cyclophosphamide IV over 1 hour and etoposide
IV over 1 hour on days 1-5 in weeks 7, 10, 19, and 25; vincristine IV once in weeks 8,
9, 11, 12, 13, 16, 22, 28, and 31; and dactinomycin IV and doxorubicin hydrochloride IV
over 15 minutes once in weeks 13, 16, 22, 28, and 31 in the absence of disease
progression or unacceptable toxicity. Patients with pulmonary metastases only who are
SIR also undergo whole lung radiotherapy once daily beginning in week 7 and continuing
for 5-14 days.

NOTE: Patients who begin study treatment after undergoing resection of pulmonary metastases
are treated according to regimen DD4A (weeks 1-25) and undergo whole lung radiotherapy for
5-14 days beginning in week 1.

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

PROJECTED ACCRUAL: A total of 400 patients will be accrued for this study.