Elias A D, Ayash L J, Eder J P, Wheeler C, Deary J, Weissman L, Schryber S, Hunt M, Critchlow J, Schnipper L
Division of Clinical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
J Clin Oncol. 1991 Feb;9(2):320-7. doi: 10.1200/JCO.1991.9.2.320.
The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.
在两项分别针对高剂量单药异环磷酰胺和卡铂的Ⅰ期试验中，剂量限制毒性分别为异环磷酰胺18 g/m²时出现肾功能不全，卡铂2400 mg/m²时出现肝毒性和耳毒性。在这项Ⅰ期研究中，16名成人接受了异环磷酰胺治疗，剂量为单药最大耐受剂量（MTD）（12 g/m²）的75%，并递增卡铂剂量（400至1600 mg/m²），以确定联合用药的非血液学剂量限制毒性和最大耐受剂量。两种药物以及用于尿路保护的美司钠均通过连续输注4天给药，美司钠额外给药1天（每个疗程总剂量为15 g/m²）。对于后续剂量水平，一旦在给定剂量水平入组的三至五名患者中有两名患者的粒细胞持续低于500/μL超过14天，则规定进行自体骨髓支持。在卡铂剂量高于400 mg/m²时使用自体骨髓支持。在卡铂最大耐受剂量水平1600 mg/m²时，肾毒性阻止了进一步的剂量递增。在该剂量水平入组的五名患者中，三名患者出现可逆性肌酐升高超过2 mg/dL（中位峰值为2.6 mg/dL），另有一名患者发生不可逆肾衰竭（肌酐峰值为6.9 mg/dL）。联合用药时短暂肉眼血尿似乎比单用异环磷酰胺更常见。两名患者出现严重嗜睡和意识模糊，同时肌酐升高。在14名经过大量预处理的可评估患者中出现了2例完全缓解（CR）和4例部分缓解（PR）（包括8例晚期难治性肉瘤可评估患者中的4例部分或完全缓解，以及2例生殖细胞癌患者中的1例CR）。卡铂和异环磷酰胺似乎具有重叠的肾毒性。然而，卡铂和异环磷酰胺可以分别以单药最大耐受剂量的80%和75%联合使用，非血液学毒性可接受。异环磷酰胺和卡铂是用于肉瘤、生殖细胞癌、卵巢癌和肺癌进一步治疗研究的有吸引力的核心联合用药方案。
