title: Phase I study of high-dose continuous intravenous infusion of VP-16 in combination with high-dose melphalan followed by autologous bone marrow transplantation in children with stage IV neuroblastoma.
abstract: The purpose of the study was to determine the maximum tolerated dose of continuous infusion of high-dose VP-16 in combination with high-dose melphalan (HDM) for conditioning before autologous bone marrow transplantation (ABMT). Thirteen children (median age 27 months) with stage IV neuroblastoma were treated with high-dose VP-16 and HDM followed by ABMT as consolidation treatment. All had previously received conventional chemotherapy with a mean number of six drugs. Surgery of the primary tumor had been performed in 12/13. We performed a dose-escalating study of VP-16 from 1800 mg/m2/72 h with 300 mg/m2/72 h dose increments according to toxicity. VP-16 was administered as a 72-h i.v. infusion. Melphalan (140 mg/m2/day) was administered once as an i.v. push. VP-16 pharmacokinetics were analyzed in 12 patients. Five children received 1800 mg/m2/72 h of VP-16, five received 2100 mg/m2/72 h and three, 2400 mg/m2/72 h. The mean duration of granulocytopenia (< 0.5 x 10(9)/1) was 24 days and thrombocytopenia (< 50 x 10(9)/1) was 36 days. No major infectious complications occurred. Gastrointestinal (GI) toxicity was the dose-limiting toxicity. Five severe manifestations of GI toxicity in three patients led us to consider 2400 mg/m2/72 h as the MTD. The mean VP-16 clearance rate was 17.3 ml/min/m2 with continuous infusion. A mean steady-state plasma concentration of 24.2 micrograms/ml (s.d. = 2) and 28.3 micrograms/ml (s.d. = 1.9) was achieved at the 1800 mg/ml and 2100 mg/m2 dose levels, respectively, GI toxicity is dose limiting when VP-16 at 2400 mg/m2/72 h, is associated with HDM. When given as a continuous i.v. infusion, at 2100 mg/m2/72 h, VP-16 associated with HDM is well tolerated before ABMT in young heavily pre-treated children.
authors.affiliation: Pediatrics Department, Institut Gustave Roussy, Villejuif, France.
authors.forename: D
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: G
authors.initials: G
authors.lastname: Vassal
authors.forename: C
authors.initials: C
authors.lastname: Pondarré
authors.forename: M
authors.initials: M
authors.lastname: Bonnay
authors.forename: E
authors.initials: E
authors.lastname: Benhamou
authors.forename: D
authors.initials: D
authors.lastname: Couanet
authors.forename: D
authors.initials: D
authors.lastname: Plantaz
authors.forename: O
authors.initials: O
authors.lastname: Hartmann
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D009503:Neutropenia / Q000139:chemically induced; D012074:Remission Induction; D016879:Salvage Therapy; D013280:Stomatitis / Q000139:chemically induced*; D019172:Transplantation Conditioning / Q000379:methods*; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin; D008558:Melphalan