HIGHLY EFFECTIVE INDUCTION THERAPY FOR STAGE-4 NEUROBLASTOMA IN CHILDREN OVER 1 YEAR OF AGE

Purpose: To test the efficacy of a protocol for poor-risk neuroblastoma that builds on the following: (1) our favorable previously reported results with dose-intensive use of cyclophosphamide; (2) our retrospective analysis of neu roblastoma chemotherapy reports, which supported the value of high-dose cisplatin and etoposide (VP-16); and (3) the Goldie-Coldman hypothesis that rapid cytoreduction plus the use of non-cross-resistant chemotherapy combinations will decrease the risk of drug resistance. Patients and Methods: The N6 protocol included seven courses of high-dose chemotherapy plus surgical resection of bulk disease. Courses 1, 2, 4, and 6 consisted of 6-hour intravenous infusions of cyclophosphamide 70 mg/kg/d on days 1 and 2 tie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/ m(2) and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m(2) intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m(2)/d on days 1 to 3 tie, 600 mg/m(2) per course), and 1-hour intravenous infusions of cisplatin 50 mg/m(2)/d on days 1 to 4 tie, 200 mg/m(2) per course). Courses were to start after neutrophil counts reached 500/mu L and platelet counts reached 100,000/mu L, Response was defined by international criteria. Results: Among 24 consecutive previously untreated patients diagnosed with stage 4 neuroblastoma at more than 1 year of age, 21 patients achieved a complete or very good partial remission; one patient had no evidence of disease except by iodine-131-metaiodobenzylguanidine (MIBG) scan, which was markedly improved; and one patient had resolution of extensive metastatic disease, but still had an incompletely resected primary tumor. The sole patient to have a poor response had clinical features at diagnosis that are atypical for neuroblastoma, namely, 8 years of age and an unknown primary tumor. Severe toxicities included myelosuppression, mucositis, and hearing deficits. Conclusion: The N6 approach reliably achieves significant cytoreduction against stage 4 neuroblastoma. This may eventuate in an improved cure rate, since consolidative treatments using myeloablative therapy, immunotherapy, or biologic response modifiers such as cis-retinoic acid are most likely to be effective against minimal residual disease. (C) 1994 by American Society of Clinical Oncology.