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


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 (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.


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.


CONCLUSIONS
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.
Kushner
B H
BH
Department of Medical Imaging, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
LaQuaglia
M P
MP
Bonilla
M A
MA
Lindsley
K
K
Rosenfield
N
N
Yeh
S
S
Eddy
J
J
Gerald
W L
WL
Heller
G
G
Cheung
N K
NK
D000008:Abdominal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced / Q000628:therapy; D006801:Humans; D007239:Infections / Q000139:chemically induced / Q000628:therapy; D008297:Male; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D017713:Platelet Transfusion; D012074:Remission Induction / Q000379:methods; D012189:Retrospective Studies; D013899:Thoracic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
D000900:Anti-Bacterial Agents; D016179:Granulocyte Colony-Stimulating Factor; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin