Bernstein M L, Whitehead V M, Devine S, Grier H, Kung F, Krischer J, Dreyer Z, Bell B, Land V, Buchanan G R
Department of Pediatrics, Montreal Children's Hospital, McGill University, Quebec, Canada.
Cancer. 1993 Sep 1;72(5):1790-4. doi: 10.1002/1097-0142(19930901)72:5<1790::aid-cncr2820720545>3.0.co;2-4.
Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors and adult acute leukemia. The authors performed a dose-escalation trial of ifosfamide with a fixed dosage of etoposide, with mesna uroprotection, in children with multiply recurrent acute leukemia.
Chemotherapy was administered daily for 5 days. Etoposide 100 mg/m2 was followed by ifosfamide at an initial dosage of 1.6 g/m2. The ifosfamide was escalated in 20% increments to the maximum tolerated dosage in cohorts of three patients. Mesna 400 mg/m2 was given immediately before the ifosfamide and then at 3 and 6 hours after ifosfamide in the initial patients. Subsequent patients were treated with mesna 400 mg/m2 just before ifosfamide, and then every 2 hours to a total dosage equal to the ifosfamide dosage.
Forty-four heavily pretreated patients were entered on study. Forty were evaluable for toxicity and 36 for response as well. The maximum tolerated dosage of ifosfamide was 4.0 g/m2/d for 5 days (20 g/m2/course). Overall, 10 patients achieved complete remission, and 3 achieved partial remission. Remissions were brief, although four patients went on to bone marrow transplant while in remission. One patient is still alive.
The combination of etoposide and ifosfamide with mesna uroprotection showed promising activity in children with multiply recurrent acute leukemia.
异环磷酰胺此前已被证明在儿科实体瘤和成人急性白血病中作为单一药物以及与阿霉素、依托泊苷和替尼泊苷联合使用时具有活性。作者对异环磷酰胺与固定剂量的依托泊苷联合使用进行了剂量递增试验，并使用美司钠进行尿路保护，用于治疗多次复发的儿童急性白血病。
化疗连续给药5天。先给予依托泊苷100mg/m²，随后给予异环磷酰胺，初始剂量为1.6g/m²。异环磷酰胺以20%的增幅递增至3名患者一组中的最大耐受剂量。最初的患者在异环磷酰胺给药前立即给予美司钠400mg/m²，然后在异环磷酰胺给药后3小时和6小时各给予一次。随后的患者在异环磷酰胺给药前给予美司钠400mg/m²，然后每2小时给药一次，总剂量等于异环磷酰胺剂量。
44名接受过大量预处理的患者进入研究。40名患者可评估毒性，36名患者可评估反应。异环磷酰胺的最大耐受剂量为4.0g/m²/天，持续5天（20g/m²/疗程）。总体而言，10名患者实现完全缓解，3名患者实现部分缓解。缓解期短暂，不过有4名患者在缓解期接受了骨髓移植。1名患者仍然存活。
依托泊苷和异环磷酰胺联合美司钠进行尿路保护在多次复发的儿童急性白血病中显示出有前景的活性。
