Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

1. Determine the response rate in children with Wilms' tumor treated with pre-operative chemotherapy.
2. Compare the response rate in children with intermediate-risk stage II or III Wilms' tumor treated with or without doxorubicin after surgery.
3. Determine the prognostic significance of histological subtypes in these patients after pre-operative chemotherapy.
4. 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.
5. Determine the prognostic significance of tumor volume and specimen weight after pre-operative chemotherapy and its relation to histological subtype in these patients.
6. Determine the effect of single-dose dactinomycin as pre-operative chemotherapy in these patients.
7. Correlate allele loss at 16q, 1p, and other chromosomal regions with relapse-free and overall survival of patients treated with these regimens.
8. Correlate allele losses with clinical risk factors (e.g., histological appearance and tumor volume) after pre-operative chemotherapy in these patients.
9. Determine laboratory indicators of myocardial damage in patients treated with these regimens.
10. 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.

Entry 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

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

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

Expected Enrollment

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

Outcomes

Event-free survival
Treatment failure, in terms of disease recurrence or death

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

Smets AM, Tinteren Hv, Bergeron C, et al.: The contribution of chest CT-scan at diagnosis in children with unilateral Wilms' tumour. Results of the SIOP 2001 study. Eur J Cancer 48 (7): 1060-5, 2012.[PUBMED Abstract]

Williams RD, Al-Saadi R, Chagtai T, et al.: Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms' tumor. Clin Cancer Res 16 (7): 2036-45, 2010.[PUBMED Abstract]

Messahel B, Williams R, Ridolfi A, et al.: Allele loss at 16q defines poorer prognosis Wilms tumour irrespective of treatment approach in the UKW1-3 clinical trials: a Children's Cancer and Leukaemia Group (CCLG) Study. Eur J Cancer 45 (5): 819-26, 2009.[PUBMED Abstract]

Warmann SW, Nourkami N, Frühwald M, et al.: Primary Lung Metastases in Pediatric Malignant Non-Wilms Renal Tumors: Data from SIOP 93-01/GPOH and SIOP 2001/GPOH. Klin Padiatr : , 2012.[PUBMED Abstract]

Furtwängler R, Nourkami N, Alkassar M, et al.: Update on relapses in unilateral nephroblastoma registered in 3 consecutive SIOP/GPOH studies - a report from the GPOH-nephroblastoma study group. Klin Padiatr 223 (3): 113-9, 2011.[PUBMED Abstract]

van den Heuvel-Eibrink MM, van Tinteren H, Rehorst H, et al.: Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr Blood Cancer 56 (5): 733-7, 2011.[PUBMED Abstract]

Warmann SW, Furtwängler R, Blumenstock G, et al.: Tumor biology influences the prognosis of nephroblastoma patients with primary pulmonary metastases: results from SIOP 93-01/GPOH and SIOP 2001/GPOH. Ann Surg 254 (1): 155-62, 2011.[PUBMED Abstract]

Szavay P, Luithle T, Graf N, et al.: Primary hepatic metastases in nephroblastoma--a report of the SIOP/GPOH Study. J Pediatr Surg 41 (1): 168-72; discussion 168-72, 2006.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

University Hospitals of Leicester NHS Trust

Jan DeKraker, MD, Protocol chair		Ph: 31-20-566-9111 Email: j.dekraker@amc.uva.nl

Societe Francaise Oncologie Pediatrique

Francois Pein, MD, Protocol chair		Ph: 33-1-4211-4339 Email: pein@igr.fr

Children's Cancer and Leukaemia Group

Kathy Pritchard-Jones, MD, Protocol chair		Ph: 44-20-8661-3452 ext 3498

Gesellschaft fuer Paediatrische Onkologie und Haematologie - Germany

Norbert Graf, Protocol chair		Ph: 49-6841-162-4000

France
	Villejuif
	Institut Gustave Roussy
		Francois Pein, MD	Ph:  33-1-4211-4339
			Email: pein@igr.fr
Germany
	Homburg
	Universitaetsklinikum des Saarlandes
		Norbert Graf	Ph:  49-6841-162-4000
Netherlands
	Amsterdam
	Academisch Medisch Centrum at University of Amsterdam
		Jan DeKraker, MD	Ph:  31-20-566-9111
			Email: j.dekraker@amc.uva.nl
United Kingdom
England
	Sutton
	Royal Marsden - Surrey
		Kathy Pritchard-Jones, MD	Ph:  44-20-8661-3452 ext 3498

Registry Information
Official Title		Nephroblastoma (Wilms Tumour) Clinical Trial And Study
Trial Start Date		2001-01-12
Registered in ClinicalTrials.gov		NCT00047138
Date Submitted to PDQ		2002-07-10
Information Last Verified		2009-06-14

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