Hochster H, Liebes L, Speyer J, Sorich J, Taubes B, Oratz R, Wernz J, Chachoua A, Raphael B, Vinci R Z
Kaplan Comprehensive Cancer Center, Division of Medical Oncology, New York University Medical Center, New York 10016.
J Clin Oncol. 1994 Mar;12(3):553-9. doi: 10.1200/JCO.1994.12.3.553.
The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer.
Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation.
The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions).
Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer.
本试验的目的是确定拓扑替康在每28天重复一次的21天输注方案中，用于癌症患者的最大耐受剂量（MTD）。
每组4名患者接受拓扑替康持续门诊输注，输注时间逐步延长，剂量从0.20mg/m²/天开始，持续7天。44例经组织学诊断为对标准治疗耐药的癌症患者接受拓扑替康输注，共115个周期，累计输注1780个患者日。每位患者的治疗周期中位数为2个（范围为1至8个）。所有患者均接受过大量化疗和/或放疗。
剂量限制性毒性（DLT）为骨髓抑制，在0.70mg/m²/天剂量水平持续21天时，血小板减少比中性粒细胞减少更明显。在MTD为0.53mg/m²时，10名患者共接受20个疗程治疗，出现1例4级血小板减少和白细胞减少、1例3级血小板减少以及2例3级白细胞减少。该剂量方案耐受性良好，非血液学毒性极小。2名患者出现局部输注端口并发症，2名患者发生菌血症，其中1名患者反复出现局部皮肤感染。在这一接受过大量治疗的人群中，观察到卵巢癌患者（6例中有2例部分缓解和1例混合缓解）、乳腺癌患者（2例中有1例部分缓解和1例混合缓解）以及肾和非小细胞肺癌各1例患者（2例部分缓解）出现客观缓解。
拓扑替康21天输注在0.53mg/m²时耐受性良好，剂量强度超过拓扑替康的其他给药方案。DLT为血液学毒性，血小板减少略超过白细胞减少。在7例乳腺癌、卵巢癌、肾癌和非小细胞肺癌患者中观察到客观缓解。
