European Infant Neuroblastoma Study Final Protocol
OBJECTIVES:
Primary
- Determine the outcome, in terms of survival and morbidity, in infants with localized,
unresectable, non-MYCN-amplified neuroblastoma treated with reduced-intensity
chemotherapy.
- Determine the survival of infants with stage 4S neuroblastoma, no MYCN amplification,
and no bone, CNS, or pleural/lung metastases treated with short-course intensive
chemotherapy.
- Determine the survival of infants with stage 4S neuroblastoma, no MYCN amplification,
and bone, CNS, or pleural/lung metastases not treated with intensive high-dose
chemotherapy consolidation.
- Determine the survival of infants with any stage (except stage 1) neuroblastoma and
MYCN amplification treated with intensive consolidation high-dose chemotherapy followed
by autologous bone marrow or stem cell support.
Secondary
- Correlate outcome with factors other than stage and MYCN status in infants with
neuroblastoma.
- Define the behavior of neuroblastoma in infants treated with these regimens.
- Determine prognostic criteria in infants treated with these regimens.
- Determine whether deletion of chromosome 1p or diploidy/tetraploidy are prognostic
factors in infants who do not have other adverse features, such as MYCN amplification.
OUTLINE: This is a nonrandomized, multicenter study. Patients are assigned to 1 of 4
treatment regimens according to disease criteria. Patients who are not eligible for any of
these regimens (stage 1 or resectable stage 2 disease) undergo surgical resection followed
by observation.
- Regimen NB 99.1 (unresectable stage 2 or 3): Patients are treated according to spinal
cord involvement and presence of neurological symptoms.
- Group I (no evidence of spinal cord involvement):
- CO therapy: Patients receive cyclophosphamide IV on days 1-5 and vincristine
IV on day 1. Treatment repeats every 14 days for up to 4 courses in the
absence of disease progression. Resectability is assessed after every 2
courses of chemotherapy; if tumor is resectable, then patients undergo
surgery followed by observation only. If, after 4 courses of CO, the tumor is
still not resectable or disease has progressed, then patients proceed to
VP-CARBO therapy.
- VP-CARBO therapy: Patients receive carboplatin IV over 1 hour and etoposide
phosphate IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2
courses. If the tumor is then deemed resectable, the patient undergoes
surgery. If the tumor is not resectable or disease has progressed, then
patients proceed to CADO therapy.
- CADO therapy: Patients receive cyclophosphamide IV over 1 hour on days 1-5,
doxorubicin hydrochloride IV over 6 hours on days 4 and 5, and vincristine IV
on days 1 and 5. Treatment repeats every 21 days for 2 courses. Patients then
proceed to resection or biopsy.
- Group II (dumbbell tumors, spinal cord compression symptoms or life-threatening
symptoms [e.g., respiratory obstruction]): Patients receive 2 courses of VP-CARBO
therapy. Patients who achieve a response proceed to surgery or biopsy if the
extraspinal portion is resectable. Patients with nonresponding disease or an
unresectable extraspinal portion of the tumor receive 2 courses of CADO therapy
and then undergo surgery or biopsy. Patients with dumbbell tumors but no spinal
cord compression symptoms are treated as in group I.
- Regimen NB 99.2 (stage 4S or stage 4 without bone, pleura/lung, or CNS metastases and
no MYCN amplification): Patients who do not have severe or life-threatening symptoms
are observed for spontaneous regression of disease. Patients with severe symptoms
receive 1 course of VP-CARBO therapy. Patients with a Philadelphia score ≥ 2 (or ≥ 1
for neonates [< 1 month old]) receive a second course of VP-CARBO therapy. If disease
does not respond to 2 courses of VP-CARBO therapy, patients receive up to 4 courses of
CADO therapy. Treatment ceases after response is obtained. Surgery is allowed but not
required.
- Regimen NB 99.3 (skeletal bone, pleural, and/or CNS metastases, no MYCN amplification):
Patients receive 2 courses of VP-CARBO therapy. Patients with responding disease
receive 2 more courses and then proceed to surgery (if possible). Patients with disease
progression or no response after the first 2 courses of VP-CARBO therapy and patients
who do not experience metastatic complete response (CR) after 4 courses of VP-CARBO
therapy receive up to 4 courses of CADO therapy. Patients proceed to surgery, if
possible, after 2-4 courses of CADO therapy.
- Regimen NB 99.4 (stages 2-4 disease with MYCN amplification): Patients receive 2
courses of VP-CARBO therapy followed by 2 courses of CADO therapy and then surgery (if
not already performed). Patients receive filgrastim (G-CSF) subcutaneously for 5 days
between the second course of CADO therapy and surgery. Patients also undergo collection
of their bone marrow or peripheral blood stem cells (PBSC). Patients who undergo
surgery receive 1 course of VP-CARBO therapy followed by 1 course of CADO therapy
postsurgery. At least 3 weeks after the third course of CADO therapy, patients receive
high-dose chemotherapy comprising busulfan every 6 hours on days -7 to -3 and melphalan
IV on day -2 followed by autologous bone marrow or PBSC infusion on day 0. At least 2
months later, patients undergo radiotherapy to the primary tumor site, even if complete
surgical resection has been accomplished. Patients with stage 4 disease who do not
achieve metastatic CR after chemotherapy (before surgery) go off study.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A total of 330 patients will be accrued for this study.
Interventional
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
Mary P. Gerrard, MBChB, FRCP, FRCPCH
Study Chair
Children's Hospital - Sheffield
United States: Federal Government
CDR0000454507
NCT00417053
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