Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age

• Published in: Journal of clinical oncology Vol. 12; no. 12; p. 2607
• Main Authors: Kushner, B H, LaQuaglia, M P, Bonilla, M A, Lindsley, K, Rosenfield, N, Yeh, S, Eddy, J, Gerald, W L, Heller, G, Cheung, N K
• Format: Journal Article
• Language: English
• Published: United States 01.12.1994
• Subjects: Abdominal Neoplasms - drug therapy; Abdominal Neoplasms - pathology; Abdominal Neoplasms - surgery; Anti-Bacterial Agents - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Child; Child, Preschool; Cisplatin - administration & dosage; Cisplatin - adverse effects; Combined Modality Therapy; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Etoposide - administration & dosage; Etoposide - adverse effects; Female; Granulocyte Colony-Stimulating Factor - administration & dosage; Hematologic Diseases - chemically induced; Hematologic Diseases - therapy; Humans; Infection - chemically induced; Infection - therapy; Male; Neoplasm Staging; Neuroblastoma - drug therapy; Neuroblastoma - secondary; Neuroblastoma - surgery; Platelet Transfusion; Remission Induction - methods; Retrospective Studies; Thoracic Neoplasms - drug therapy; Thoracic Neoplasms - pathology; Thoracic Neoplasms - surgery; Vincristine - administration & dosage; Vincristine - adverse effects
• ISSN: 0732-183X
• DOI: 10.1200/JCO.1994.12.12.2607

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 neuroblastoma 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. 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 (ie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/m2 and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m2 intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m2/d on days 1 to 3 (ie, 600 mg/m2 per course), and 1-hour intravenous infusions of cisplatin 50 mg/m2/d on days 1 to 4 (ie, 200 mg/m2 per course). Courses were to start after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Response was defined by international criteria. 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. 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.