Trial Information

Nephroblastoma (Wilms Tumour) Clinical Trial And Study

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.