Price T, Hill M
GI Unit, Royal Marsden Hospital, Sutton, United Kingdom.
Oncology (Williston Park). 2000 Oct;14(10 Suppl 9):28-31.
UFT (with leucovorin) and irinotecan both have single-agent activity in colorectal cancer, with non-cross-resistant mechanisms of action. Combining these drugs would be anticipated to increase response rates while maintaining the advantages of a regimen based on an orally administered fluoropyrimidine. This trial aims to determine the maximum tolerated dose, side-effect profile, dose-limiting toxicity, and response rate for the combination of UFT plus leucovorin, and irinotecan. The design is for an initial phase I study investigating escalating doses of UFT (250 to 350 mg/m2/d) and irinotecan (200 to 300 mg/m2) with fixed doses of leucovorin at 90 mg/d, in up to five cohorts of six patients each. UFT and leucovorin are given orally on days 1 to 14 of a 21-day cycle and irinotecan is given intravenously on day 1. The maximum tolerated dose is defined as the dose at which three of six patients in a cohort have a dose-limiting toxicity in the first cycle of treatment. In the second part of the study, the cohort below that experiencing maximum tolerated dose will be expanded up to a total of 20 patients in order to assess further the toxicity and response rate (phase II). To date, 17 assessable patients have been recruited, with a median age of 64 years (range: 35-80 years). At the first dose level (UFT 250 mg/m2/d and irinotecan 200 mg/m2), no dose-limiting toxicities were seen, and in cohort 2 (UFT 250 mg/m2/d and irinotecan 250 mg/m2), there was one grade 3 diarrhea. In cohort 3 (UFT 250 mg/m2/d and irinotecan 300 mg/m2), currently there have been two grade 3/4 toxicities (both neutropenic fever). Thus, the maximum tolerated dose has not yet been reached. Response has been assessed in the first six patients, with three having partial response, two having stable disease, and one having progressive disease (response rate 50%). We conclude that this regimen appears feasible with acceptable toxicity at these dose levels. There is also evidence of significant antitumor activity similar to that seen with other fluoropyrimidine-based combination regimens but without the requirement for indwelling catheters or inpatient admission.
优福定（联合亚叶酸）和伊立替康在结直肠癌治疗中均具有单药活性，且作用机制无交叉耐药。联合使用这些药物有望提高缓解率，同时保留基于口服氟嘧啶方案的优势。本试验旨在确定优福定联合亚叶酸与伊立替康联合用药的最大耐受剂量、副作用特征、剂量限制性毒性及缓解率。试验设计为初始的I期研究，研究递增剂量的优福定（250至350mg/m²/天）和伊立替康（200至300mg/m²），亚叶酸固定剂量为90mg/天，共分为多达五个队列，每个队列6名患者。优福定和亚叶酸在21天周期的第1至14天口服，伊立替康在第1天静脉给药。最大耐受剂量定义为一个队列中6名患者中有3名在第一个治疗周期出现剂量限制性毒性时的剂量。在研究的第二部分，低于最大耐受剂量的队列将扩大至总共20名患者，以进一步评估毒性和缓解率（II期）。迄今为止，已招募了17名可评估患者，中位年龄为64岁（范围：35 - 80岁）。在第一个剂量水平（优福定250mg/m²/天和伊立替康200mg/m²），未观察到剂量限制性毒性，在队列2（优福定250mg/m²/天和伊立替康250mg/m²），出现1例3级腹泻。在队列3（优福定250mg/m²/天和伊立替康300mg/m²），目前已有2例3/4级毒性反应（均为中性粒细胞减少性发热）。因此，尚未达到最大耐受剂量。已对前6名患者进行了疗效评估，3例部分缓解，2例病情稳定，1例病情进展（缓解率50%）。我们得出结论，在这些剂量水平下，该方案似乎可行，毒性可接受。也有证据表明该方案具有显著的抗肿瘤活性，类似于其他基于氟嘧啶的联合方案，但无需留置导管或住院治疗。
