Combination Chemotherapy in Treating Infants With Newly Diagnosed Neuroblastoma Who Are Undergoing Surgery With or Without Autologous Bone Marrow or Peripheral Stem Cell Transplant

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.