Elias A D, Ayash L J, Wheeler C, Schwartz G, Tepler I, McCauley M, Mazanet R, Schnipper L, Frei E, Antman K H
Division of Clinical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Semin Oncol. 1994 Oct;21(5 Suppl 12):83-5.
Agents with broad cytotoxic activity, steep linear log dose-response relationships, relative non-cross-resistance, and nonoverlapping nonhematologic toxicities can be combined to create new high-dose combination regimens. We have previously reported phase I dose-escalation studies of ifosfamide, carboplatin, and the combination of the two. Etoposide has reported synergism with these alkylators and produces mucositis as its dose-limiting toxicity. The current study was designed to define the maximum tolerated doses of high-dose combination ifosfamide/carboplatin/etoposide (ICE), with stem cell support for amelioration of hematologic toxicity. Forty-eight adults with advanced malignancy received ICE chemotherapy by 96-hour continuous infusion. Initially, etoposide was added to fixed-dose ifosfamide and carboplatin, then the maximum tolerated dose of etoposide was fixed while doses of the alkylators were individually escalated. Autologous marrow, with or without peripheral blood progenitor cells, was reinfused 3 days after completing chemotherapy. The maximum tolerated doses of ifosfamide, carboplatin, and etoposide were identified as 16 g/m2, 1.8 g/m2, and 1.2 g/m2, respectively. Mortality was 4%. Patients who had prior cisplatin exposure were at increased risk for renal toxicity. If serum creatinine levels (monitored twice daily) rose sharply during chemotherapy, ifosfamide and carboplatin were immediately stopped. Severe multiorgan toxicity developed in the few patients who experienced early renal toxicity. Early stopping enhanced the safety of this regimen. Interpatient differences in chemotherapy drug metabolism or reduced renal clearance may predispose individuals to severe toxicity by increasing overall drug exposure. It was concluded that the ICE regimen is well tolerated and warrants further exploration as treatment of patients with small cell lung cancer, ovarian and germ cell carcinomas, and lymphomas in phase II trials.
具有广泛细胞毒性活性、陡峭的线性对数剂量-反应关系、相对无交叉耐药性以及非重叠非血液学毒性的药物可联合使用，以创建新的高剂量联合方案。我们之前曾报告过异环磷酰胺、卡铂以及两者联合的I期剂量递增研究。依托泊苷已被报道与这些烷化剂具有协同作用，并以黏膜炎作为其剂量限制性毒性。当前研究旨在确定高剂量联合异环磷酰胺/卡铂/依托泊苷（ICE）的最大耐受剂量，并采用干细胞支持来改善血液学毒性。48名晚期恶性肿瘤成人患者接受了96小时持续输注的ICE化疗。最初，依托泊苷被添加到固定剂量的异环磷酰胺和卡铂中，然后在依托泊苷的最大耐受剂量固定的情况下，分别递增烷化剂的剂量。在完成化疗3天后回输自体骨髓，可伴有或不伴有外周血祖细胞。异环磷酰胺、卡铂和依托泊苷的最大耐受剂量分别确定为16 g/m²、1.8 g/m²和1.2 g/m²。死亡率为4%。既往接受过顺铂治疗的患者发生肾毒性的风险增加。如果化疗期间血清肌酐水平（每日监测两次）急剧上升，则立即停用异环磷酰胺和卡铂。少数出现早期肾毒性的患者发生了严重的多器官毒性。早期停药提高了该方案的安全性。化疗药物代谢的个体间差异或肾清除率降低可能会通过增加总体药物暴露使个体易发生严重毒性。得出的结论是，ICE方案耐受性良好，值得在II期试验中进一步探索用于治疗小细胞肺癌、卵巢癌和生殖细胞癌以及淋巴瘤患者。
