Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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.

PURPOSE: This phase III clinical trial is studying how well combination chemotherapy and surgery work in treating young patients with Wilms tumor.

Further Study Information

OBJECTIVES:

• To improve 4-year event-free survival to 73% for young patients with bilateral Wilms tumor (BWT) treated with induction chemotherapy, surgery, and postoperative chemotherapy.

• To prevent complete removal of at least one kidney in 50% of patients with BWT by using vincristine sulfate, dactinomycin, and doxorubicin hydrochloride as preoperative induction chemotherapy.

• To evaluate the efficacy of chemotherapy in preserving renal units and preventing Wilms tumor development in patients with diffuse hyperplastic perilobular nephrogenic rests.

• To facilitate partial nephrectomy in lieu of total nephrectomy in 25% of patients with unilateral Wilms tumor and aniridia, Beckwith-Wiedemann syndrome, hemihypertrophy, or other overgrowth syndromes by using vincristine sulfate and dactinomycin as preoperative induction chemotherapy.

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

OUTLINE: This is a multicenter study.

• 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). Patients on EE-4A will NOT receive radiation therapy.

• 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).NOTE: *Omit week 25 doxoubicin dose if patient received 6 or 12 weeks of Regimen VAD.

• 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; and stage II-IV unilateral WT with diffuse 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, WT arising in a solitary kidney [patients with metachronous WT are excluded]): 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.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Synchronous or metachronous bilateral Wilms tumor (BWT)*

• Unilateral Wilms tumor (WT) 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)

• Multicentric WT (any age)

• To be eligible, these patients must not undergo any nephrectomy at diagnosis

• Multicentric WT or unilateral WT with contralateral nephrogenic rest(s) (any size) in a patient < 1 year of age

• To be eligible, these patients must not undergo any nephrectomy at diagnosis

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

• WT arising in a solitary kidney

• Patients with metachronous WT are not eligible NOTE: *It is often difficult to distinguish WT from nephrogenic rests based on imaging studies and percutaneous biopsies. The AREN0534 study uses the guideline that WT 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 WT stratum. Patients with an isolated lesion less than 1 cm in the contralateral kidney should be treated on the appropriate study for unilateral WT OR on the unilateral WT/contralateral nephrogenic rest stratum of this study if they have not undergone nephrectomy and are under one year of age.

• Patients with BWT who underwent total or partial nephrectomy at diagnosis are eligible

• Previously enrolled in COG-AREN03B2

• Loss of heterozygosity (LOH) results—which are used in the unilateral WT studies—are not a requirement for enrollment on AREN0534

• Patients must begin protocol therapy by Day 14 following surgery or diagnosis by initial CT/MRI, unless medically contraindicated

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) or Lansky PS 50-100% (for patients ≤ 16 years of age)

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

• AST or ALT < 2.5 times ULN for age

• Shortening fraction ≥ 27% by ECHO 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)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior systemic chemotherapy or radiotherapy

• No concurrent aprepitant

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Peter F. Ehrlich

Study Chair

U.S.A.
New Jersey
	New Brunswick
	Saint Peter's University Hospital
		Stanley Calderwood	Ph: 732-745-8600ext6163
			Email: kcovert@saintpetersuh.com

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Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00945009
Information obtained from ClinicalTrials.gov on April 04, 2013

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