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Antimitotic Agents

dactinomycin

carboplatin

cyclophosphamide

doxorubicin hydrochloride

etoposide

vincristine sulfate

adjuvant therapy

conventional surgery

neoadjuvant therapy

radiation therapy

Francois Pein, MD

Norbert Graf

Jan DeKraker, MD

Kathy Pritchard-Jones, MD

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.

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.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

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

Chemotherapy Before and After Surgery in Treating Children With Wilm's Tumor

Nephroblastoma (Wilms Tumour) Clinical Trial And Study

Societe Francaise Oncologie Pediatrique

Children's Cancer and Leukaemia Group

German Society for Pediatric Oncology and Hematology GPOH gGmbH

University of Leicester

DNA methylation analysis

gene expression analysis

loss of heterozygosity analysis

microarray analysis

mutation analysis

polymerase chain reaction

reverse transcriptase-polymerase chain reaction

laboratory biomarker analysis

Elizabeth J. Perlman, MD

RATIONALE: Studying samples of tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and identify biomarkers related to cancer.

PURPOSE: This clinical trial studies biomarkers in tumor tissue samples from young patients with very low risk Wilms tumors.

OBJECTIVES:

* To validate the utility of CUGBP2, HMGA2, and MEIS2 mRNA expression and 11p15 methylation to define a population of pediatric patients with very low risk Wilms tumor (VLRWT) that have virtually no risk of relapse.
* To validate the utility of WT-1 mutation and 11p15 loss of heterozygosity analysis to determine a population of VLRWT that have a higher risk of relapse when not treated with chemotherapy.
* To validate the utility of NFYA, STRA6, TOB2, PDCD4, and SP3 mRNA expression to predict relapse in VLRWT.
* To investigate the feasibility of broadening the definition of VLRWT through analysis of stage I and II epithelial differentiated tumors registered on clinical trial COG-Q9401 (NWTS-5) for CUGBP2, HMGA2, MEIS2, and 11p15 methylation.

OUTLINE: Previously banked tumor tissue samples are analyzed for mRNA expression of CUGBP2, HMGA2, and MEIS2 via reverse-transcriptase (RT)-PCR and are classified as loss of heterozygosity (LOH), loss of imprinting, or neither via 11p15 analysis. Samples are also analyzed for WT-1 mutation via quantitative PCR and 11p LOH using 11p15 methylation analysis and expression of NFYA, STRA6, TOB2, PDCD4, and SP3 via quantitative RT-PCR

Biomarkers in Tumor Tissue Samples From Young Patients With Very Low Risk Wilms Tumors

Validation of Prognostic Markers for Very Low Risk Wilms Tumors

National Cancer Institute (NCI)

Children's Oncology Group

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy Before and After Surgery in Treating Children With Wilm's Tumor	NCT00047138	Kidney Cancer	dactinomycin carboplatin cyclophosphamid... doxorubicin hyd... etoposide vincristine sul... adjuvant therap... conventional su... neoadjuvant the... radiation thera...	- 18 Years	National Cancer Institute (NCI)
Chemotherapy Before and After Surgery in Treating Children With Wilm's Tumor	NCT00047138	Kidney Cancer	dactinomycin carboplatin cyclophosphamid... doxorubicin hyd... etoposide vincristine sul... adjuvant therap... conventional su... neoadjuvant the... radiation thera...	- 18 Years	National Cancer Institute (NCI)
Biomarkers in Tumor Tissue Samples From Young Patients With Very Low Risk Wilms Tumors	NCT01004783	Kidney Cancer	DNA methylation... gene expression... loss of heteroz... microarray anal... mutation analys... polymerase chai... reverse transcr... laboratory biom...	- 18 Years	Children's Oncology Group

Spots Global Cancer Trial Database for epithelial predominant wilms tumor