Lokich J
Cancer Center of Boston, Massachusetts 02120, USA.
Am J Clin Oncol. 2001 Aug;24(4):336-40. doi: 10.1097/00000421-200108000-00003.
Combining antineoplastic analogues may increase efficacy by increasing the serum and intracellular concentration of the cytotoxic moiety shared by the analogues. Topotecan and irinotecan are two camptothecan analogues that are active in different human tumors (topotecan in ovary; irinotecan in colon) and in different experimental tumor systems. These data suggest that different mechanisms of drug resistance may be operative for the two agents, and if incomplete cross-resistance exists between analogues, concomitant administration may be advantageous. The objectives of this phase I study were 1) to determine in a phase trial design whether topotecan and irinotecan administered concomitantly on a weekly schedule can be delivered at the same dose intensity as that of single-agent topotecan or irinotecan delivery; and 2) to determine whether hematologic and/or nonhematologic toxicity is increased with topotecan and irinotecan administered together as a prelude to a possible phase II trial in responsive tumor categories. Irinotecan was administered for 30 to 45 minutes weekly x 4 at four dose levels: 50, 75, 100, and 125 mg/m(2)/wk. Topotecan was administered for 30 minutes (after irinotecan administration) at two dose levels within each of the irinotecan dose levels (1.0 and 1.5 mg/m(2)). Concomitant single-dose granulocyte-macrophage colony-stimulating factor (G-CSF) was used for leukocyte counts between 1,000 cells/mm(3) and 3,500 cells/mm(3) to maintain schedule. Maximum tolerated dosage (MTD) for the topotecan and irinotecan combination was defined as that which permitted 4 weeks of topotecan and irinotecan administration with G-CSF at or near the dose intensity reported for each single agent. Twenty-one patients received 32 4-week cycles. Dose-limiting toxicity was hematologic with grade IV leukopenia and neutropenia occurring at all dose levels. There was no apparent increase in the diarrhea syndrome associated with irinotecan. The MTD for irinotecan (at 125 mg/m(2)/wk) is the same MTD as with single-agent irinotecan use. The MTD for concomitant topotecan (1.5 mg/m(2)/wk) is 60% of the single-agent topotecan dose for the 5-day topotecan schedule (at 2.5 mg/m(2)/wk) but only 30% of the single-agent topotecan dose for the weekly schedule (5 mg/m(2)/wk). The topoisomerase I inhibitor dose is increased minimally when the analogues are administered concomitantly on a weekly schedule. Comparative trials of single-agent topotecan and irinotecan versus the combination of topotecan and irinotecan would be necessary to provide the proof of principle that combining analogues can increase therapeutic effectiveness.
联合使用抗肿瘤类似物可通过提高类似物共有的细胞毒性部分在血清和细胞内的浓度来增强疗效。拓扑替康和伊立替康是两种喜树碱类似物，它们在不同的人类肿瘤（拓扑替康用于卵巢癌；伊立替康用于结肠癌）以及不同的实验性肿瘤系统中具有活性。这些数据表明，两种药物可能存在不同的耐药机制，并且如果类似物之间存在不完全交叉耐药性，联合给药可能具有优势。本I期研究的目的是：1）在I期试验设计中确定，每周一次同时给予拓扑替康和伊立替康，是否能达到与单药拓扑替康或伊立替康给药相同的剂量强度；2）确定作为可能的II期试验用于反应性肿瘤类型的前奏，同时给予拓扑替康和伊立替康时血液学和/或非血液学毒性是否增加。伊立替康每周给药30至45分钟，共4周，分四个剂量水平：50、75、100和125mg/m²/周。在每个伊立替康剂量水平内，拓扑替康在两个剂量水平（1.0和1.5mg/m²）下于伊立替康给药后30分钟给药。对于白细胞计数在1000个细胞/mm³至3500个细胞/mm³之间的患者，使用单剂量的粒细胞巨噬细胞集落刺激因子（G-CSF）以维持给药计划。拓扑替康和伊立替康联合使用的最大耐受剂量（MTD）定义为允许在有或接近每种单药报告的剂量强度下，使用G-CSF同时给予拓扑替康和伊立替康4周的剂量。21名患者接受了32个4周疗程。剂量限制性毒性为血液学毒性，所有剂量水平均出现IV级白细胞减少和中性粒细胞减少。与伊立替康相关的腹泻综合征没有明显增加。伊立替康的MTD（125mg/m²/周）与单药使用伊立替康时相同。同时使用的拓扑替康的MTD（1.5mg/m²/周）对于5天拓扑替康给药计划（2.5mg/m²/周）而言是单药拓扑替康剂量的60%，但对于每周给药计划（5mg/m²/周）而言仅为单药拓扑替康剂量的30%。当类似物每周同时给药时，拓扑异构酶I抑制剂的剂量增加极少。有必要对单药拓扑替康和伊立替康与拓扑替康和伊立替康联合使用进行对比试验，以提供联合类似物可提高治疗效果的原理证明。
