Topotecan preceded by oxaliplatin using a 3 week schedule: a phase I study in advanced cancer patients
Topotecan preceded by oxaliplatin using a 3 week schedule: a phase I study in advanced cancer patients
复制标题
DOI：
10.1016/s0959-8049(02)00232-0
复制
发表时间：
2002-09-01
影响因子：
8.4
通讯作者：
Goldwasser, F
中科院分区：
文献类型：
--
作者：
Gross-Goupil, M;Lokiec, F;Goldwasser, F
拓扑异构酶I（topo 1）毒物和铂衍生物的组合具有协同抗肿瘤作用。然而，其临床开发受到超累加血液学毒性的限制。本研究的目的是确定拓扑替康和奥沙利铂的持续剂量是否可以使用协同序列实现。34例晚期癌症患者和186个周期可评价5个剂量水平的毒性。第1天给予奥沙利铂85-110 mg/m2，随后从第1天至第5天给予拓扑替康0.5-1.25 mg/m2/天x 5，每3周一次。在第一个周期测定总铂和超滤铂、总拓扑替康和内酯形式的血浆药代动力学（PK）。剂量限制性毒性（DT）被确定为4级血小板减少症。4级血小板减少症的发生与拓扑替康PK无关，但与患者特征相关。1/8例无营养不良的临床或生物学证据、肌酐清除率高于1 ml/s、既往化疗方案不超过2次的患者出现重度血小板减少，而8/10例具有上述特征之一的患者出现重度血小板减少（P < 0.004）。总之，奥沙利铂110 mg/m2和托泊替康1 mg/m2/天的推荐剂量每3周一次可用于一般状况和治疗前特征良好的患者，值得在卵巢癌患者中进行11期研究。(C)2002爱思唯尔科技有限公司。保留所有权利。
Combinations of topoisomerase I (topo 1) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim or this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day I to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than I ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P < 0.004). In conclusion, the recommended doses of oxaliplatin 110 mg/m(2) and topotecan 1 mg/m(2)/day, every 3 weeks can be administered to patients with a favourable general status and pretreatment characteristics and a phase 11 study is worthwhile in ovarian cancer patients. (C) 2002 Elsevier Science Ltd. All rights reserved.