Ohtsu T, Sasaki Y, Igarashi T, Murayama T, Kobayashi Y, Tobinai K
Department of Medicine, National Cancer Center Hospital East, Chiba, Japan.
Jpn J Clin Oncol. 1998 Aug;28(8):502-6. doi: 10.1093/jjco/28.8.502.
Irinotecan (CPT-11) is a topoisomerase I inhibitor that has been confirmed to be active against a broad spectrum of neoplasms including non-Hodgkin's lymphoma (NHL). Because the combination of topoisomerase I and II inhibitors seemed to be an attractive therapeutic strategy owing to their complementary functions, we conducted a combination phase I study of CPT-11 and etoposide, a topoisomerase II inhibitor, in relapsed or refractory non-Hodgkin's lymphoma (NHL).
The starting doses of CPT-11 and etoposide were 30 mg/m2/day (days 1-3 and 8-10) and 40 mg/m2 (days 1-3), respectively.
All three patients who received the starting dose developed dose-limiting toxicities including one case of grade 4 neutropenia lasting for > 7 days, one of grade 3 serum transaminase elevation and one of grade 3 hyperbilirubinemia. All three patients presented hepatotoxicity > or = grade 2. The starting dose level was judged to be the maximum tolerated dose (MTD) and further dose escalation of this combination was halted. The patient who developed grade 3 hyperbilirubinemia presented a second peak of plasma SN-38, an active metabolite of CPT-11, on the concentration-time curve for day 3, suggesting the possibility of the enterohepatic circulation of SN-38 and of a drug-to-drug interaction. No durable objective response was observed in the three patients treated at the starting dose.
We conclude that etoposide is not recommended for combination with CPT-11 in NHL patients because of unexpected frequent hepatotoxicities.
伊立替康（CPT - 11）是一种拓扑异构酶I抑制剂，已被证实对包括非霍奇金淋巴瘤（NHL）在内的多种肿瘤具有活性。由于拓扑异构酶I和II抑制剂的功能互补，联合使用似乎是一种有吸引力的治疗策略，因此我们开展了一项伊立替康与拓扑异构酶II抑制剂依托泊苷联合用于复发或难治性非霍奇金淋巴瘤（NHL）的I期研究。
伊立替康和依托泊苷的起始剂量分别为30mg/m²/天（第1 - 3天和第8 - 10天）和40mg/m²（第1 - 3天）。
所有接受起始剂量的3例患者均出现剂量限制性毒性，包括1例4级中性粒细胞减少持续超过7天、1例3级血清转氨酶升高和1例3级高胆红素血症。所有3例患者均出现≥2级肝毒性。起始剂量水平被判定为最大耐受剂量（MTD），该联合用药方案停止进一步剂量递增。出现3级高胆红素血症的患者在第3天的浓度 - 时间曲线上血浆SN - 38（CPT - 11的活性代谢产物）出现第二个峰值，提示SN - 38存在肠肝循环以及药物相互作用的可能性。接受起始剂量治疗的3例患者均未观察到持久的客观缓解。
我们得出结论，由于出现意外频繁的肝毒性，不建议在NHL患者中将依托泊苷与伊立替康联合使用。
