Mathew P, Ribeiro R C, Sonnichsen D, Relling M, Pratt C, Mahmoud H, Bowman L, Meyer W, Avery L, Crist W
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38101-0318.
J Clin Oncol. 1994 Jul;12(7):1452-7. doi: 10.1200/JCO.1994.12.7.1452.
To determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and plasma concentrations of orally administered etoposide (VP-16) in pediatric oncology patients.
In a phase I study, 20 children with refractory solid tumors received oral VP-16 (the intravenous preparation diluted with sodium chloride) three times daily for 21 days. Daily dose levels studied were 50 mg/m2 (n = 5), 60 mg/m2 (n = 7), and 75 mg/m2 (n = 8). VP-16 concentrations were measured in blood samples collected on days 1, 7, 14, and 21.
Grade 3 to 4 thrombocytopenia and/or neutropenia causing interruption of the 21-day course or persisting for more than 7 days after the last day of chemotherapy was seen at all dose levels, but was not dose-limiting. One patient treated at the 50-mg/m2 daily dose died of sepsis. At the 75-mg/m2 dose level, diarrhea was dose-limiting. Estimated plasma VP-16 concentrations were greater than 1 micrograms/mL for median periods of 9.4, 15.4, and 13.5 hours per day at daily doses of 50, 60, and 75 mg/m2, respectively. Responses were observed in seven of 14 patients who received at least one additional course of etoposide after a rest period of 7 days. There was one complete and two objective responses. Four patients were considered to have stable disease.
The intravenous preparation of VP-16 administered orally appears to be well tolerated by heavily pretreated pediatric patients. On the three-times daily, 21-day schedule, a daily dose of 75 mg/m2 exceeds the MTD, with diarrhea as the dose-limiting toxicity. The recommended dose for oral etoposide is 60 mg/m2/d administered every 8 hours.
确定口服依托泊苷（VP - 16）在儿科肿瘤患者中的最大耐受剂量（MTD）、剂量限制性毒性和血浆浓度。
在一项I期研究中，20例难治性实体瘤儿童患者接受口服VP - 16（用氯化钠稀释的静脉制剂），每日3次，共21天。研究的每日剂量水平分别为50mg/m²（n = 5）、60mg/m²（n = 7）和75mg/m²（n = 8）。在第1、7、14和21天采集的血样中测量VP - 16浓度。
在所有剂量水平均观察到3至4级血小板减少和/或中性粒细胞减少，导致21天疗程中断或在化疗最后一天后持续超过7天，但并非剂量限制性毒性。一名接受每日50mg/m²剂量治疗的患者死于败血症。在75mg/m²剂量水平，腹泻是剂量限制性毒性。在每日剂量为50、60和75mg/m²时，估计血浆VP - 16浓度分别在每天的中位时间9.4、15.4和13.5小时内大于1μg/mL。在14例患者中有7例在休息7天后接受至少一个额外疗程的依托泊苷治疗后出现反应。有1例完全缓解和2例客观缓解。4例患者被认为病情稳定。
口服VP - 16的静脉制剂似乎能被经过大量预处理的儿科患者良好耐受。在每日3次、共21天的给药方案中，每日剂量75mg/m²超过了MTD，腹泻为剂量限制性毒性。口服依托泊苷的推荐剂量为60mg/m²/天，每8小时给药一次。
