Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
This phase III trial studies how well combination chemotherapy and surgery work in treating
 young patients with Wilms tumor. Drugs used in chemotherapy work in different ways to stop
 the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill
 more tumor cells. Giving combination chemotherapy before surgery may make the tumor smaller
 and reduce the amount of normal tissue that needs to be removed. Giving it after surgery may
 kill any tumor cells that remain after surgery.
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: Patients are assigned to 1 of 3 arms.

 ARM 1 (Bilateral Wilms Tumors): Patients start with three drug chemotherapy (Regimen VAD;
 vincristine, dactinomycin and doxorubicin) and are evaluated and six and 12 weeks for
 feasibility of undergoing a partial nephrectomy/renal sparing surgery. At week 12 definitive
 surgery takes place followed by chemotherapy and radiation therapy based on histology and
 stage. Treatment continues for 25 or 31 weeks depending on histology. Patients are followed
 for up to 10 years following end of therapy.

 ARM 2 (Unilateral High Risk tumors bilaterally predisposed): Patients start with either 2
 drug or three drug chemotherapy (Regimen VA, VAD) and are evaluated a 6 and 12 weeks for
 feasibility of undergoing a partial nephrectomy. At week 12 definitive surgery takes place
 followed by chemotherapy.

 ARM 3 (DHPLN): Patients with this rare disease are diagnosed based on cross-sectional imaging
 characteristics and undergo 2 drug chemotherapy (Regimen;VA). Patients are reassessed at 6
 weeks and 12 weeks. If disease has responded or stayed stable chemotherapy is completed for
 19 weeks (Regimen EE4A). If disease has progress a biopsy is performed to assess histology
 and adjust therapy based on the biopsy. This therapy may include, nephrectomy, chemotherapy
 or radiation therapy.

 VAD REGIMEN: Patients receive vincristine sulfate intravenously (IV) over 1 minute 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).

 EE4A REGIMEN: 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).

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

 -  The patient must have one of the following conditions to be eligible:

 -  Synchronous bilateral Wilms tumors**; or

 -  Unilateral Wilms tumor and aniridia, Beckwith-Wiedemann Syndrome, idiopathic
 hemihypertrophy, Simpson-Golabi-Behmel-Syndrome, Denys-Drash Syndrome or other
 associated genitourinary anomalies associated with bilateral Wilms tumor, such as
 hypospadias and undescended testis (to be eligible, these patients must not
 undergo any nephrectomy at diagnosis; note-horseshoe kidney is not associated
 with bilateral Wilms tumor and these patients should go on the appropriate
 unilateral Wilms tumor study); or

 -  Multicentric Wilms tumor (any age) (to be eligible, these patients must not
 undergo any nephrectomy at diagnosis); or

 -  Unilateral Wilms tumor with contralateral nephrogenic rest(s) (any size) in a
 child under one year of age (to be eligible, these patients must not undergo any
 nephrectomy at diagnosis); or

 -  Diffuse hyperplastic perilobar nephroblastomatosis (unilateral or bilateral)
 defined by central radiological review; or

 -  Wilms tumor arising in a solitary kidney (patients with metachronous Wilms tumor
 are not eligible)

 -  The AREN0534 study uses the guideline that Wilms tumor with a single lesion
 1 cm or greater in the contralateral kidney or multiple lesions (of any
 size) in the contralateral kidney should be treated on the synchronous
 bilateral Wilms tumor stratum; patients with an isolated lesion less than 1
 cm in the contralateral kidney should be treated on the appropriate study
 for unilateral Wilms tumor OR on the unilateral Wilms tumor/contralateral
 nephrogenic rest stratum of this study if they have not undergone
 nephrectomy and are under one year of age

 -  Loss of heterozygosity (LOH) results?which are used in the unilateral Wilms tumor
 studies?are not a requirement for enrollment on AREN0534; blood samples can be
 submitted but will not be used to direct AREN0534 therapy

 -  Specimens/materials must be submitted for central review by day 7; for enrollment on
 AREN0534, unless a biopsy was done, the submission requirements at enrollment on
 AREN03B2 refer to imaging studies; tissue samples are only required if a surgical
 procedure (biopsy or nephrectomy) was performed at the time of enrollment on AREN03B2

 -  Patients must begin protocol therapy on AREN0534 by day 14 following surgery or
 diagnosis by initial computed tomography (CT)/magnetic resonance imaging (MRI), unless
 medically contraindicated

 -  Karnofsky performance status must be >= 50% for patients > 16 years of age and Lansky
 performance status must be >= 50% (for patients =< 16 years of age

 -  Patients must not have received systemic chemotherapy or radiation therapy prior to
 treatment on this study

 -  Patients with unilateral Wilms tumor and aniridia, Beckwith-Wiedemann Syndrome,
 idiopathic hemihypertrophy, Simpson-Golabi-Behmel-Syndrome, Denys-Drash Syndrome or
 other associated genitourinary anomalies; or multicentric or unilateral Wilms tumor
 with contralateral nephrogenic rest(s) (any size) in a child under 1 year of age who
 undergo a nephrectomy at diagnosis are not eligible for this study and should be
 directed to a unilateral Wilms tumor study

 -  Total bilirubin =< 1.5 times upper limit of normal (ULN) for age

 -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5
 times upper limit of normal (ULN) for age

 -  Shortening fraction >= 27% by echocardiogram, OR ejection fraction >= 50% by
 radionuclide angiogram

 -  (Cardiac function does not need to be assessed in patients who will not receive
 doxorubicin as part of their initial therapy on this study [i.e., patients who
 start on regimen EE-4A])

 -  Female patients of childbearing age must have a negative pregnancy test

 -  Female patients who are lactating must agree to stop breastfeeding

 -  Sexually active patients of childbearing potential must agree to use effective
 contraception

 -  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

 -  No concurrent aprepitant