Coordinated use of sequentially escalated cyclophosphamide and cell-cycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: experience with 100 patients.

Abstract

A rationally devised induction regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and sequentially-escalated cyclophosphamide (CPM), followed by S-phase-specific agents (5-fluorouracil [5-FU]/cytosine arabinoside [ara-C]/hydroxyurea), was used in 100 patients with neuroblastoma. Of 17 patients under 1 year of age at diagnosis, complete (CR)/good partial (GPR) responses with long-term disease-free survival were achieved in 11 (85%) of 13 new patients and in two of four previously treated patients; six of the GPRs also received myeloablative therapy with autologous bone marrow rescue to consolidate remission status. The 83 patients over 1 year of age at diagnosis included three groups: (1) 36 new patients whose N4SE included maximal-dose CPM (ie, up to 140 to 160 mg/kg/course); (2) an earlier group of 18 new patients whose N4SE included moderate-dose CPM (ie, up to 80 mg/kg/course); and (3) 29 previously treated patients who all received the maximal-dose N4SE regimen. For new patients, CR/GPR rates were 72% in the maximal-dose group v 39% in the earlier moderate-dose group (P = .029). A CR/GPR rate of 41% and a partial response rate of 17% were observed for the 29 previously treated patients, all but two of whom had large tumor burdens after therapy that included moderate doses of CPM. Despite consolidation with myeloablative therapy, many responders in the three groups ultimately relapsed. The N4SE was strongly myelosuppressive, but only two patients died from associated infection. Extramedullary toxicity was limited to hemorrhagic cystitis in four of 33 CPM previously treated patients; this problem did not occur in the 67 new patients. The data indicate that the maximal-dose N4SE is an effective induction regimen for neuroblastoma, can achieve marked regressions of disease resistant to less intensive therapy, and is sparing of major body organs. This high rate of remission induction must be coupled with improvements in consolidation therapy to assure long-term disease-free survival of poor-risk patients.