Etoposide and Cisplatin in Treating Young Patients With Previously Untreated High-Risk Neuroblastoma Undergoing High-Dose Chemotherapy Stem Cell Transplant and Isotretinoin

Description

OBJECTIVES: Primary - Estimate the response rate associated with two courses of cisplatin and protracted oral etoposide when administered as up-front window therapy to pediatric patients with previously untreated high-risk neuroblastoma undergoing high-dose chemotherapy and stem cell rescue followed by maintenance therapy comprising isotretinoin. - Describe the toxicities associated with cisplatin and protracted oral etoposide when administered as up-front window therapy to these patients. Secondary - Evaluate the induction response rates, patterns of treatment failure, event-free survival , and overall survival of children with high-risk neuroblastoma treated with this regimen. - Evaluate the feasibility and toxicity of resection of primary tumors after two courses of induction chemotherapy. - Describe the antiangiogenic effects of cisplatin and protracted oral etoposide in these patients. - Estimate the change in neuropsychological assessment battery in children > 2 years old at diagnosis and correlate these changes with toxicities of therapy. - Provide a consistent treatment strategy as a platform for the study of biologic features of the tumor and patient. OUTLINE: This is a multicenter study. - Induction therapy: Courses of induction therapy are 21 days in duration. - Courses 1, 2, and 4: Patients receive cisplatin IV over 6 hours on days 1-5 and oral protracted etoposide* once daily on days 1-14. Patients with responding disease after course 2 receive cisplatin and oral protracted etoposide as above during course 4. Patients with stable disease, residual disease, or progressive disease after course 2 receive cisplatin IV over 6 hours and etoposide IV over 1 hour on days 2-4 during course 4. - Courses 3 and 5: Patients receive cyclophosphamide IV over 6 hours and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 3 and continuing until blood counts recover. Patients undergo peripheral blood stem cell collection after course 3. NOTE: *Patients who are ineligible to participate or choose not to participate in the phase II window (e.g., treatment with oral protracted etoposide) receive cisplatin as above and etoposide IV over 1 hour on days 2-4 during courses 1, 2, and 4. - Consolidation therapy: - Radiotherapy: Beginning within 6 weeks after starting the final course of induction therapy, patients undergo radiotherapy for local control of neuroblastoma (approximately 2,400 cGy in 12 doses). Patients then proceed to high-dose chemotherapy and stem cell rescue (HDT/SCR). - HDT/SCR: Beginning within 1-2 weeks after completion of radiotherapy, patients receive carboplatin IV continuously and etoposide IV continuously on days -7 to -4 and melphalan IV on days -7 to -5. Patients undergo SCR with autologous peripheral blood progenitor cells on day 0. Patients also receive G-CSF SC once daily beginning on day 5 and continuing until blood counts recover. - Maintenance therapy: Beginning on day 90 after HDT/SCR, patients with responding disease receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses. - Surgery: Patients undergo delayed surgical resection of the primary tumor after course 2 of induction therapy if the tumor is considered resectable. If the tumor is not considered resectable after course 2 of induction therapy, a reevaluation of the primary tumor should occur after course 3 and again after course 5 of induction therapy, if needed. Blood and tissue samples are collected for correlative studies. Tissue samples are analyzed by immunohistochemistry, microvessel density assessment, and molecular techniques for angiogenic factors (VEGF and MMP-9). Blood samples are analyzed for the presence of circulating endothelial cells and angiogenesis factors. Patients receiving oral protracted etoposide who are ≥ 2 years of age at diagnosis and proceed to consolidation therapy undergo neuropsychological assessment after course 2 of induction therapy, annually until 8 years of age, and then clinician choice of annually or every other year (based on test results). After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.

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