Hurwitz C A, Relling M V, Weitman S D, Ravindranath Y, Vietti T J, Strother D R, Ragab A H, Pratt C B
Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN.
J Clin Oncol. 1993 Dec;11(12):2324-9. doi: 10.1200/JCO.1993.11.12.2324.
A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed.
Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation.
A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%.
Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.
开展一项I期研究，以描述紫杉醇（泰素；百时美施贵宝公司，康涅狄格州沃灵福德）对难治性实体瘤患儿的主要毒性，并确定其最大耐受剂量（MTD）。此外，研究了紫杉醇在儿童体内的药代动力学情况，并评估了紫杉醇对儿童实体瘤活性的初步证据。
每21天对患有难治性实体瘤的儿童（中位年龄12岁；范围2至22岁）进行一次24小时持续输注紫杉醇。剂量范围为200至420mg/m²，未在患者内进行剂量递增。
共对31例患者给予了62个疗程的紫杉醇。两名患者分别在第二次输注紫杉醇时出现急性过敏反应，剂量分别为200mg/m²和350mg/m²。未记录到其他过敏反应。所有剂量水平均出现骨髓抑制，但持续时间较短（≤7天），且未随连续疗程或更高剂量水平而增加。剂量≥290mg/m²时出现手套-袜套样周围神经病变。420mg/m²时出现剂量限制性神经毒性，一名患者出现明显的精细运动和周围神经病变，另一名患者出现强直-阵挛性癫痫发作。输注结束时血浆浓度范围为0.40至6.4μmol/L，在所研究的剂量范围内未发现其与剂量相关。记录到1例完全缓解、2例部分缓解和1例轻微缓解，总缓解率为13%。
对复发实体瘤的儿科患者进行24小时持续输注紫杉醇时，神经毒性是剂量限制性的。在该人群中，II期试验的推荐剂量为350mg/m²/天。
