Shepherd F A, Latreille J, Crump M, Stewart D, Tomiak E, Eisenhauer E, Fisher B
Department of Medicine, Toronto Hospital, Canada.
Ann Oncol. 1996 Mar;7(3):311-3. doi: 10.1093/oxfordjournals.annonc.a010577.
Paclitaxel (Taxol) and ifosfamide are among the most active single agents for the treatment of non-small-cell lung cancer. We undertook this phase I dose escalation study to determine the maximum tolerated doses of these drugs which could be administered without growth factors to untreated patients with tumours of this type.
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 every 3 weeks. Groups of 3 patients were entered at escalating dose levels in traditional phase I design. Starting doses were paclitaxel, 100 mg/m2, and ifosfamide 3 g/m2, and all patients received premedication with dexamethasone, diphenhydramine and a 5-HT3 blocker. Dose escalation occurred only after full toxicity assessment for 2 cycles for all patients in the 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 neuro-toxicity above this level. Instead, ifosfamide was increased to 4 g/m2 for the final level. At these doses, dose-limiting myelosuppression was not seen, and there was only 1 episode of febrile neutropenia in 164 treatment cycles. Drug-related toxicities of ifosfamide included gross hematuria and confusion in 1 patient each, and paclitaxel-related symptoms included flu-like syndrome in most patients, mild to moderate arthralgia and/or myalgia in 8 and 25 patients, respectively, parasthesiae in 15 patients and mild to moderate hypersensitivity reactions in 15 patients each. Partial response was seen in 20.5% of patients (CI 9.3%-36.5%).
Out-patient paclitaxel given over 3 hours and single-dose ifosfamide over 1 hour may be combined safely without the need for 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.
紫杉醇（泰素）和异环磷酰胺是治疗非小细胞肺癌最有效的单一药物。我们开展了这项I期剂量递增研究，以确定在不使用生长因子的情况下，可给予此类未治疗肿瘤患者的这两种药物的最大耐受剂量。
40例晚期非小细胞肺癌患者每3周接受一次3小时的紫杉醇输注和1小时的异环磷酰胺输注。按照传统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，异环磷酰胺3g/m²，所有患者均接受地塞米松、苯海拉明和5 - HT3受体阻滞剂预处理。仅在对剂量水平的所有患者进行2个周期的全面毒性评估后才进行剂量递增。
紫杉醇剂量递增至225mg/m²时未出现剂量限制性毒性，但由于已知高于此水平有神经毒性的可能性，未尝试进一步递增剂量。相反，将异环磷酰胺在最后一个剂量水平增至4g/m²。在这些剂量下，未观察到剂量限制性骨髓抑制，在164个治疗周期中仅出现1例发热性中性粒细胞减少。异环磷酰胺的药物相关毒性包括1例患者出现肉眼血尿和1例患者出现意识模糊，紫杉醇相关症状包括大多数患者出现类流感综合征，分别有8例和25例患者出现轻度至中度关节痛和/或肌痛，15例患者出现感觉异常，各有15例患者出现轻度至中度过敏反应。20.5%的患者出现部分缓解（95%置信区间9.3% - 36.5%）。
3小时静脉输注门诊用紫杉醇和1小时单剂量异环磷酰胺可安全联合使用，无需造血生长因子来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，异环磷酰胺4g/m²，每3周一次。
