Pazdur R, Lassere Y, Diaz-Canton E, Bready B, Ho D H
Division of Medicine, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Invest New Drugs. 1997;15(2):123-8. doi: 10.1023/a:1005808822565.
We previously reported results of a Phase II trial of UFT [Taiho Pharmaceutical Ltd., Tokyo, Japan; (BMS-200604) Bristol-Myers Squibb, Princeton, NJ], an oral 4:1 molar concentration of uracil and tegafur, plus oral leucovorin for metastatic colorectal carcinoma (Pazdur et al., J. Clin. Oncol. 12:2296-2300, 1994]. Our results demonstrated that a 28-day schedule of this combination produced a response rate similar to that obtained with conventional intravenous fluorouracil (5-FU)-plus-leucovorin regimens but without the severe or life-threatening neutropenia or oral mucositis that complicates intravenous 5-FU regimens. The current Phase I trial examines the dose-limiting toxic effects and maximum tolerated dose of a 14-consecutive-day schedule of UFT plus oral leucovorin in 14 patients who had histologically proven cancer and had received prior chemotherapy. The daily UFT plus leucovorin dose was divided into three doses administered orally every 8 hours. In this study, the UFT dose was escalated while the leucovorin dose remained at 150 mg/day. Of the 14 patients, 4 were initially treated at the 350-mg/m2/day UFT level for 14 days without any dose-limiting toxic reactions. Subsequently, another 7 patients were treated at the 400-mg/m2/day level; grade 3 diarrhea developed in 3 of these 7 (with severe abdominal cramping in 2 cases and severe nausea and vomiting unresponsive to antiemetics in the third). To better define the starting dose for phase II studies, an additional 3 patients were treated at the 350-mg/m2/day dose level. Of the total 7 patients treated at 350 mg/m2/day, grade 3 toxic events (diarrhea) developed in 2 patients. Grade 1-2 toxic effects noted at this level included fatigue, stomatitis, skin rash, abdominal pain, nausea, and vomiting. Neither partial nor complete responses were observed in this trial. The maximum tolerated dose of this schedule is 350 mg/m2/day UFT plus 150 mg/day oral leucovorin. However, because of this schedule's inferior dose intensity compared with that of the 28-day schedule of UFT plus leucovorin, subsequent development of UFT in the United States has focused on the 28-day regimen.
我们之前报道了一项关于优福定[日本东京大鹏药品工业株式会社；（BMS - 200604）美国新泽西州普林斯顿市百时美施贵宝公司]的II期试验结果，优福定是尿嘧啶与替加氟按4:1摩尔浓度配比的口服制剂，联合口服亚叶酸用于治疗转移性结直肠癌（帕兹杜尔等人，《临床肿瘤学杂志》12:2296 - 2300, 1994年）。我们的结果表明，这种联合用药方案28天疗程的缓解率与传统静脉注射氟尿嘧啶（5 - FU）加亚叶酸方案相似，但不会出现使静脉注射5 - FU方案复杂化的严重或危及生命的中性粒细胞减少或口腔黏膜炎。当前的I期试验研究了优福定联合口服亚叶酸连续14天给药方案在14例经组织学证实患有癌症且之前接受过化疗的患者中的剂量限制性毒性作用和最大耐受剂量。优福定加亚叶酸的每日剂量分为每8小时口服一次的三个剂量。在本研究中，优福定剂量逐步递增，而亚叶酸剂量保持在150毫克/天。14例患者中，4例最初在优福定350毫克/平方米/天的剂量水平治疗14天，未出现任何剂量限制性毒性反应。随后，另外7例患者在400毫克/平方米/天的剂量水平接受治疗；这7例中有3例出现3级腹泻（其中2例伴有严重腹痛，第3例伴有严重恶心呕吐且对抗呕吐药无反应）。为了更好地确定II期研究的起始剂量，另外3例患者在350毫克/平方米/天的剂量水平接受治疗。在350毫克/平方米/天剂量水平接受治疗的7例患者中，有2例出现3级毒性事件（腹泻）。该剂量水平观察到的1 - 2级毒性作用包括疲劳、口腔炎、皮疹、腹痛、恶心和呕吐。在该试验中未观察到部分缓解或完全缓解。此给药方案的最大耐受剂量是优福定350毫克/平方米/天加口服亚叶酸150毫克/天。然而，由于该给药方案与优福定加亚叶酸28天给药方案相比剂量强度较低，优福定在美国随后的研发重点放在了28天疗程方案上。
