RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy before surgery may shrink the tumor so it can be removed during surgery. Giving more chemotherapy after surgery may kill any remaining tumor cells. It is not yet known which chemotherapy regimen after surgery is most effective in treating Wilm's tumor.

PURPOSE: Phase III trial to study the effectiveness of chemotherapy before and after surgery in treating children who have Wilm's tumor.

Condition	Treatment or Intervention	Phase
Wilms' Tumor Wilms' tumor and other childhood kidney tumors	Drug: carboplatin  Drug: cyclophosphamide  Drug: dactinomycin  Drug: doxorubicin  Drug: etoposide  Drug: vincristine  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: neoadjuvant therapy  Procedure: radiation therapy  Procedure: surgery	Phase III

Further Study Details: 

OBJECTIVES:

• Determine the response rate in children with Wilms' tumor treated with pre-operative chemotherapy.
• Compare the response rate in children with intermediate-risk stage II or III Wilms' tumor treated with or without doxorubicin after surgery.
• Determine the prognostic significance of histological subtypes in these patients after pre-operative chemotherapy.
• Determine whether reduced treatment minimizes acute and late toxicity without jeopardizing event-free and overall survival in patients with focal anaplasia or intermediate-risk stage I Wilms' tumor.
• Determine the prognostic significance of tumor volume and specimen weight after pre-operative chemotherapy and its relation to histological subtype in these patients.
• Determine the effect of single-dose dactinomycin as pre-operative chemotherapy in these patients.
• Correlate allele loss at 16q, 1p, and other chromosomal regions with relapse-free and overall survival of patients treated with these regimens.
• Correlate allele losses with clinical risk factors (e.g., histological appearance and tumor volume) after pre-operative chemotherapy in these patients.
• Determine laboratory indicators of myocardial damage in patients treated with these regimens.
• Determine the prognostic significance of the percentage of necrosis after pre-operative chemotherapy, in terms of type and amount of residual viable tumor, in these patients.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified according to country and participating center. Patients with intermediate-risk stage II or III disease are further stratified according to histology (blastemal vs epithelial vs stromal vs mixed).

Patients with localized disease receive neoadjuvant therapy comprising vincristine IV on days 1, 8, 15, and 22 and dactinomycin IV on days 1 and 15.

Patients undergo surgery during weeks 5 or 6.

Patients with low-risk stage I disease receive no further therapy.

Adjuvant chemotherapy begins after surgery and within 21 days of last dose of neoadjuvant chemotherapy.

Patients with intermediate-risk stage I disease receive vincristine IV on days 1, 8, 15, and 22 and dactinomycin IV on day 7.

Patients with intermediate-risk stage II or III disease are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive vincristine IV weekly for 8 weeks and then on days 1 and 7 of weeks 11, 14, 17, 20, 23, and 26. Patients also receive dactinomycin IV weekly on weeks 2, 5, 8, 11, 14, 17, 20, 23, and 26 and doxorubicin IV over 4-6 hours weekly on weeks 2, 8, 14, 20, and 26.
• Arm II: Patients receive vincristine and dactinomycin as in arm I. Patients with high-risk stage I disease receive chemotherapy as in arm I. Patients with low-risk stage II disease receive chemotherapy as in arm II.

Patients with high-risk stage II or III disease receive cyclophosphamide IV over 1 hour on days 1-3 and doxorubicin IV over 4-6 hours on day 1 on weeks 1, 7, 13, 19, 25, and 31. Patients also receive etoposide IV over 4 hours and carboplatin IV over 1 hour on days 1-3 on weeks 4, 10, 16, 22, 28, and 34.

Patients with intermediate-risk stage III or high-risk stage II or III disease also undergo radiotherapy for approximately 3 weeks during chemotherapy.

Patients with metastatic disease receive neoadjuvant chemotherapy comprising vincristine IV on day 1 of weeks 1-6, dactinomycin IV on day 1 of weeks 1, 3, and 5, and doxorubicin IV over 4-6 hours on day 1 of weeks 1 and 5.

Patients undergo surgery during week 7.

Within 2 weeks of surgery patients receive 1 of the following adjuvant chemotherapy regimens:

• Regimen A (no metastases or completely resected): Patients receive vincristine IV weekly for 8 weeks and then on weeks 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27. Patients also receive dactinomycin IV on day 1 of weeks 2, 5, 8, 11, 14, 17, 20, 23, and 26 and doxorubicin IV over 4-6 hours on weeks 2, 8, 14, and 20. Some patients also undergo radiotherapy concurrently with chemotherapy for approximately 3 weeks.
• Regimen B (multiple inoperable metastases, incomplete resection, or high-risk primary disease): Patients receive etoposide IV over 4 hours and carboplatin IV over 1 hour on days 1-3 of weeks 4, 10, 13, 16, 22, 25, 28, and 34. Patients also receive cyclophosphamide IV over 1 hour on days 1-3 and doxorubicin IV over 4-6 hours on day 1 of weeks 1, 7, 19, and 31. Some patients also undergo radiotherapy concurrently with chemotherapy for approximately 3 weeks. Patients are followed every 2-3 months for 2 years, every 3-6 months for 1-2 years, and then every 6-12 months thereafter.

PROJECTED ACCRUAL: A total of 350 patients (174 per treatment arm) will be accrued for the randomized portion of this study within 7 years.

Ages Eligible for Study:  up to  18 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following:
• Localized disease
• Unilateral tumor
• Histologically confirmed Wilms' tumor OR
• Clinical and ultrasonic characteristics of nephroblastoma
• No metastasis
• Age 6 months to 17 years at diagnosis
• No prior anticancer therapy
• Metastatic disease
• Unilateral tumor
• Histologically confirmed Wilms' tumor OR
• Clinical and ultrasonic characteristics of nephroblastoma
• Age 18 and under
• No prior anticancer therapy
• Simultaneous bilateral tumors
• No metastases
• No recurrent disease
• No other renal tumors

PATIENT CHARACTERISTICS: Age

• See Disease Characteristics
• 18 and under

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• No social or geographical reasons that would preclude study
• No other associated pathology that would preclude study

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• No prior surgery
• No requirement for emergency or immediate surgery for any reason

France
      Institut Gustave Roussy, Villejuif,  94805 CEDEX,  France; Recruiting
Germany
      Universitatsklinik - Saarland, HOMBURG / SAAR,  D-66421,  Germany; Recruiting
Netherlands
      Academisch Medisch Centrum, Amsterdam,  1100 DE,  Netherlands; Recruiting
United Kingdom, England
      Royal Marsden NHS Foundation Trust - Surrey, Sutton,  England,  SM2 5PT,  United Kingdom; Recruiting

Study chairs or principal investigators

Jan DeKraker, MD,  Study Chair,  Academisch Medisch Centrum   
Francois Pein, MD,  Study Chair,  Institut Gustave Roussy   
Kathy Pritchard-Jones, MD,  Study Chair,  Royal Marsden NHS Trust   
N. Graf,  Study Chair,  Universitatsklinik - Saarland   

Study ID Numbers:  CDR0000257531; SIOP-WT-2001; SFOP-SIOP-WT-2001; UKCCSG-SIOP-WT-2001; GPOH-GERMANY-SIOP-WT-2001; EU-20208; NCT00047138
Record last reviewed:  September 2003
Last Updated:  December 6, 2004
Record first received:  October 3, 2002
ClinicalTrials.gov Identifier:  NCT00047138
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08