Vassal G, Tranchand B, Valteau-Couanet D, Mahé C, Couanet D, Schoeppfer C, Grill J, Kalifa C, Hill C, Ardiet C, Hartmann O
Department of Paediatric Oncology, Institut Gustave-Roussy, Villejuif, France.
Bone Marrow Transplant. 2001 Mar;27(5):471-7. doi: 10.1038/sj.bmt.1702806.
Repeated high-dose (HD) chemotherapy with peripheral blood stem cell (PBSC) transplantation is a new modality aimed at increasing both the dose and its intensity in the treatment of chemosensitive tumours. The aim of this study was to evaluate the tolerance, pharmacokinetics (PK) and pharmacodynamics (PD) of HD single-agent melphalan administered over two consecutive courses (C1 and C2) in children. Twenty-one patients (10 girls) with a median age of 4.1 years (range 8 months-14 years) were entered into this study. Five had metastatic neuroblastoma (NB) and 16 a cerebral primitive neuroectodermal tumour (PNET). Melphalan was given at a dose of 100 mg/m(2) every 21 days. PBSCs were infused at a median number of 2.98 x 10(6) CD34(+) cells/kg. Forty courses, ie 21 C1 and 19 C2, were administered. Both courses were well tolerated. The median duration of ANC < 500/microl was 7 and 6 days after C1 and C2, respectively. Platelet recovery (not mandatory to continue the HD strategy) was achieved in 52% of courses. GI toxicity was mild to moderate. The melphalan AUC ranged from 177 to 475 microg small middle dotmin/ml (no difference between C1 and C2). Prolonged neutropenia was associated with a young age (P < 0.001) and a low amount of CFU-GM (P = 0.002). A long time to platelet recovery was associated with a high AUC (P = 0.004) and a young age (P = 0.02). Grade 1 or 2 GI toxicity was associated with a high AUC (P = 0.015). Partial remission was observed in 11/14 patients with measurable cerebral PNET. In conclusion, tandem HD melphalan is feasible and safe in children, and achieved a high response rate in cerebral PNET. The observed PK-PD relationships may help us design PK-guided outpatient treatment.
重复大剂量（HD）化疗联合外周血干细胞（PBSC）移植是一种旨在增加化疗敏感肿瘤治疗剂量及其强度的新方法。本研究的目的是评估连续两个疗程（C1和C2）给予儿童HD单药美法仑的耐受性、药代动力学（PK）和药效动力学（PD）。21例患者（10名女孩）进入本研究，中位年龄4.1岁（范围8个月至14岁）。5例患有转移性神经母细胞瘤（NB），16例患有脑原始神经外胚层肿瘤（PNET）。美法仑每21天给予100mg/m²的剂量。PBSC输注的中位数量为2.98×10⁶个CD34⁺细胞/kg。共进行了40个疗程，即21个C1疗程和19个C2疗程。两个疗程耐受性均良好。C1和C2疗程后中性粒细胞绝对值（ANC）<500/μl的中位持续时间分别为7天和6天。52%的疗程实现了血小板恢复（继续HD策略并非必需）。胃肠道毒性为轻至中度。美法仑的曲线下面积（AUC）范围为177至475μg·min/ml（C1和C2之间无差异）。长期中性粒细胞减少与年龄小（P<0.001）和集落形成单位-粒细胞-巨噬细胞（CFU-GM）数量低（P=0.002）有关。血小板恢复时间长与AUC高（P=0.004）和年龄小（P=0.02）有关。1或2级胃肠道毒性与AUC高（P=0.015）有关。14例可测量的脑PNET患者中有11例观察到部分缓解。总之，串联HD美法仑在儿童中可行且安全，并在脑PNET中取得了高缓解率。观察到的PK-PD关系可能有助于我们设计以PK为指导的门诊治疗。
