Elias A D, Eder J P, Shea T, Begg C B, Frei E, Antman K H
Division of Clinical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
J Clin Oncol. 1990 Jan;8(1):170-8. doi: 10.1200/JCO.1990.8.1.170.
Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.
异环磷酰胺的II期试验采用了5至8g/m²/疗程的标准剂量。在这项I期研究中，29例患者接受了为期4天的异环磷酰胺持续输注，以确定最大耐受剂量和非血液学剂量限制性毒性。如果在给定剂量水平的两至五名患者中有两名患者的粒细胞计数超过500/μL超过14天，则将使用自体骨髓支持进行后续剂量水平的治疗。异环磷酰胺的剂量从8g/m²逐步增加至18g/m²。美司钠以等效剂量持续输注5天。在18g/m²剂量水平时，观察到剂量限制性肾功能不全以及粒细胞减少（低于500/μL）的中位持续时间为11天（范围为8至18天）。因此，未使用自体骨髓再输注。骨髓抑制的持续时间、粘膜炎的频率和严重程度以及肾小管酸中毒均呈剂量依赖性。轻度至中度中枢神经系统毒性似乎也与剂量有关；然而，在低剂量和高剂量水平均偶尔观察到严重的中枢神经系统毒性（短暂性意识模糊、幻觉和嗜睡）。短暂性血尿（每高倍视野超过50个红细胞）仅出现过一次，但未影响治疗。在27例经过大量预处理的可评估患者中有9例有反应（2例完全缓解），其中包括20例晚期难治性肉瘤患者中的7例有反应。异环磷酰胺联合美司钠进行尿路保护，在遇到非血液学剂量限制性毒性之前，可以比通常规定的剂量进行相当程度的剂量递增。异环磷酰胺对实体瘤具有广泛的细胞毒性，可能会被证明是高剂量联合化疗方案中的重要补充。
