Shepherd F A, Latreille J, Paul K, Eisenhauer E
Department of Medicine, The Toronto Hospital, Hotel-Dieu de Montreal and The National Cancer Institute of Canada, Clinical Trials Group, Kingston, Ontario.
Semin Oncol. 1996 Dec;23(6 Suppl 16):84-90.
This phase I dose-escalation study was undertaken to determine the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and ifosfamide that could be administered without growth factors to previously untreated patients with non-small cell lung cancer. Forty patients with advanced non-small cell lung cancer were treated with a 3-hour infusion of paclitaxel and a 1-hour infusion of ifosfamide, repeated every 3 weeks. Groups of three patients each entered at escalating dose levels in a traditional phase I design. Starting doses were paclitaxel 100 mg/m2 and ifosfamide 3 g/m2; all patients received premedication with dexamethasone and diphenhydramine, and some also received a 5-HT3 blocker. Dose escalation was permitted only after full toxicity assessment had been completed for two cycles for all patients at a dose level. Dose escalation of paclitaxel continued to 225 mg/m2 without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neurotoxicity above this dosage. Instead, ifosfamide was increased to 4 g/m2 for the final dose level. At these doses, dose-limiting myelosuppression was not seen, and there was only one episode of febrile neutropenia in 162 treatment cycles. Drug-related ifosfamide toxicities included gross hematuria and confusion in one patient each; paclitaxel-related symptoms included flu-like syndrome in most patients, arthralgia and/or myalgia in eight and 25 patients, respectively, and paresthesia in 14 patients. Despite premedication, 15 patients experienced grade 1 hypersensitivity reactions. Partial response was seen in 21% of patients (confidence interval, 9.3% to 36.5%), and the median duration of response was 5.9+ months (range, 3 to 14 months). The median survival was 9.1 months (range, 1 to 12 months). In summary, outpatient paclitaxel given over 3 hours and single-dose ifosfamide given over 1 hour may be combined safely without hematopoietic growth factors for the treatment of patients with non-small cell lung cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and ifosfamide 4 g/m2, every 3 weeks.
本I期剂量递增研究旨在确定在不使用生长因子的情况下，可给予既往未接受过治疗的非小细胞肺癌患者的紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）和异环磷酰胺的最大耐受剂量。40例晚期非小细胞肺癌患者接受3小时的紫杉醇输注和1小时的异环磷酰胺输注，每3周重复一次。按照传统的I期设计，每组3例患者以递增剂量水平入组。起始剂量为紫杉醇100mg/m²和异环磷酰胺3g/m²；所有患者均接受地塞米松和苯海拉明预处理，部分患者还接受了5-羟色胺3受体阻滞剂。仅在对某一剂量水平的所有患者完成两个周期的全面毒性评估后才允许剂量递增。紫杉醇剂量递增至225mg/m²时未出现剂量限制性毒性，但由于已知高于此剂量时神经毒性的可能性增加，未尝试进一步递增剂量。相反，将异环磷酰胺的最终剂量水平增至4g/m²。在这些剂量下，未观察到剂量限制性骨髓抑制，在162个治疗周期中仅出现1例发热性中性粒细胞减少。与药物相关的异环磷酰胺毒性包括1例患者出现肉眼血尿和1例患者出现意识障碍；与紫杉醇相关的症状包括大多数患者出现类流感综合征，分别有8例和25例患者出现关节痛和/或肌痛，14例患者出现感觉异常。尽管进行了预处理，仍有15例患者出现1级过敏反应。21%的患者出现部分缓解（置信区间为9.3%至36.5%），缓解的中位持续时间为5.9+个月（范围为3至14个月）。中位生存期为9.1个月（范围为1至12个月）。总之，3小时静脉输注紫杉醇和1小时静脉输注单剂量异环磷酰胺可在不使用造血生长因子的情况下安全联合，用于治疗非小细胞肺癌患者。II期研究的推荐剂量为紫杉醇225mg/m²和异环磷酰胺4g/m²，每3周一次。
