Trial Information

Treatment for Patients With Bilateral, Multicentric, or Bilaterally-Predisposed Unilateral Wilms Tumor

OBJECTIVES:

I. To improve 4-year event-free survival (EFS) to 73% for young patients with bilateral
Wilms tumor (BWT).

II. To prevent complete removal of at least one kidney in 50% of patients with BWT by using
prenephrectomy 3-drug chemotherapy induction with vincristine (vincristine sulfate),
dactinomycin, and doxorubicin (doxorubicin hydrochloride).

III. To evaluate the efficacy of chemotherapy in preserving renal units in children with
diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and preventing Wilms tumor
development.

IV. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with
unilateral tumors and aniridia, Beckwith-Wiedemann syndrome (BWS), hemihypertrophy or other
overgrowth syndromes, by using prenephrectomy 2-drug chemotherapy induction with vincristine
and dactinomycin.

V. To have 75% of patients with BWT undergo definitive surgical treatment by 12 weeks after
initiation of chemotherapy.

OUTLINE:

PREOPERATIVE CHEMOTHERAPY: Patients receive preoperative chemotherapy according to histology
and stage.

VAD REGIMEN (stage I-IV bilateral Wilms tumor [BWT] with biopsy revealing favorable
histology or no preoperative biopsy; stage I-III BWT with focal anaplasia; stage I BWT with
diffuse anaplasia; or high-risk, stage III-IV unilateral Wilms tumor [WT] with contralateral
nephrogenic rest [NR] or predisposition syndrome): Patients receive vincristine sulfate IV
on days 1, 8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV and doxorubicin
hydrochloride IV over 15-120 minutes on days 1 and 22 (weeks 1 and 4).

REVISED UH-1 REGIMEN (stage IV BWT with focal anaplasia; stage II-IV BWT with diffuse
anaplasia; or stage I-IV malignant rhabdoid tumor of the kidney): Patients receive
vincristine sulfate IV on days 1, 8, and 15 (weeks 1-3); doxorubicin hydrochloride IV over
15-120 minutes on day 1 (week 1); cyclophosphamide IV over 1 hour on day 1 and on days 22-25
(weeks 1 and 4); carboplatin IV over 1 hour on day 22 (week 4); and etoposide phosphate IV
over 1 hour on days 22-25 (week 4).

EE-4A REGIMEN (high-risk, stage I-II unilateral WT with contralateral NR or predisposition
syndrome or diffuse hyperplastic perilobar NRs [DHPLNR]): Patients receive vincristine
sulfate IV over 1 minute on days 1, 8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV
over 1-5 minutes on days 1 and 22 (weeks 1 and 4).

Patients are evaluated at week 6. If partial nephrectomy is feasible, patients proceed to
definitive surgery and lymph node sampling followed by postoperative therapy. If partial
nephrectomy is not feasible, patients receive additional chemotherapy (as above with the
same or a different set of regimen) followed by definitive surgery at week 12 and
postoperative therapy OR patients proceed to a different chemotherapy regimen.

POSTOPERATIVE THERAPY: Patients receive postoperative therapy according to histology after
preoperative chemotherapy and according to the highest assigned risk for either kidney.

EE-4A regimen (BWT with complete resection of all gross tumors at diagnosis with stage I-II
favorable histology; BWT with complete response [CR] by imaging after 6 weeks of
preoperative chemotherapy; completely necrotic stage I-II BWT; intermediate-risk stage I
BWT; unilateral WT stage I-II with CR by imaging after 6-12 weeks of preoperative
chemotherapy; completely necrotic stage I-II unilateral WT; or intermediate-risk stage I-II
unilateral WT): Patients receive vincristine sulfate IV over 1 minute on days 43, 50, 57,
64, 85, 106, and 127 (weeks 7-10, 13, 16, and 19) and dactinomycin IV over 1-5 minutes on
days 43, 64, 85, 106, and 127 (weeks 7, 10, 13, 16, and 19).

DD-4A REGIMEN (intermediate-risk, stage II BWT; stage I BWT with blastemal predominance; or
stage I unilateral WT with blastemal predominance): Patients receive vincristine sulfate IV
over 1 minute on days 1, 8, 15, 22, 29, and 36 (weeks 1-6); dactinomycin IV over 1-5 minutes
on day 1 (week 1); and doxorubicin hydrochloride IV over 15-120 minutes on day 22 (week 4).
Patients then receive vincristine sulfate IV over 1 minute on days 43, 50, 57, 64, 85, 106,
127, 148, and 169 (weeks 7-10, 13, 16, 19, 22, and 25); dactinomycin IV over 1-5 minutes on
days 43, 85, 127, and 169 (weeks 7, 13, 19, and 25); and doxorubicin hydrochloride over
15-120 minutes on days 63, 106, and 148 (weeks 10, 16, and 22). Some patients may also
undergo radiotherapy.

DD-4A REGIMEN AND RADIOTHERAPY (BWT with complete resection of all gross tumors at diagnosis
with stage III-IV favorable histology, completely necrotic stage III-IV BWT;
intermediate-risk, stage III-IV BWT; stage I BWT with diffuse anaplasia; stage I-III BWT
with focal anaplasia; stage I unilateral WT with diffuse anaplasia; stage I unilateral WT
with focal anaplasia; or intermediate-risk, stage III-IV unilateral WT): Patients receive
DD-4A regimen as above. Patients also undergo concurrent radiotherapy.

REGIMEN I (stage II BWT with blastemal predominance or stage II unilateral WT with blastemal
predominance): Patients receive vincristine sulfate IV over 1 minute on days 43, 50, 57, 71,
78, 85, 92, 127, and 169 (weeks 7-9, 11-14, 19, and 25); doxorubicin hydrochloride IV over
15-120 minutes on days 43, 85, 127, and 169 (weeks 7, 13, 19, and 25); cyclophosphamide IV
over 15-30 minutes on days 43, 64, 85, 106, 127, 148, and 169 (weeks 7, 10, 13, 16, 19, 22,
and 25); and etoposide phosphate IV over 1 hour on days 64, 106, and 148 (weeks 10, 16, and
22).

REGIMEN I AND RADIOTHERAPY (stage III-IV BWT with blastemal predominance or stage III-IV
unilateral WT with blastemal predominance): Patients receive regimen I as above. Patients
also undergo concurrent radiotherapy.

REVISED UH-1 REGIMEN AND RADIOTHERAPY (stage IV BWT with focal anaplasia; stage II-IV BWT
with diffuse anaplasia; stage IV unilateral WT with focal anaplasia; stage II-IV unilateral
WT with diffuse anaplasia; and stage I-IV malignant rhabdoid tumor of the kidney; or DHPLNR
with anaplasia): Patients receive vincristine sulfate IV over 1 minute on days 64, 71, 78,
85, 92, 99, 148, 155, 162, 190, 197, and 204 (weeks 10-15, 22-24, and 28-30); doxorubicin
hydrochloride IV over 15-120 minutes on days 64, 85, 148, and 190 (weeks 10, 13, 22, and
28); cyclophosphamide IV over 15-30 minutes on days 43-46, 64, 85, 106-109, 127-130, 148,
169-172, and 190 (weeks 7, 10, 13, 16, 19, 22, 25, and 28); carboplatin IV over 1 hour on
days 43, 106, 127, and 169 (weeks 7, 16, 19, and 25); and etoposide phosphate IV over 1 hour
on days 43-46, 106-109, 127-130, and 169-172 (weeks 7, 16, 19, and 25). Patients also
undergo radiotherapy.

VAD REGIMEN (DHPLNR with favorable histology WT with viable elements): Patients receive
vincristine sulfate IV over 1 minute on days 43, 50, 57, 64, 71, and 78 (weeks 7-12) and
dactinomycin IV over 1-5 minutes and doxorubicin hydrochloride IV over 15-120 minutes on
days 43 and 64 (weeks 7 and 10).

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