Childs H A, Spencer S A, Raben D, Bonner J A, Newsome J, Robert F
University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA.
Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):939-44. doi: 10.1016/s0360-3016(00)00496-x.
This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level.
Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6.
Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15.
Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.
本I期研究将替加氟尿嘧啶（UFT）与亚叶酸钙及传统放疗联合用于治疗胰腺癌。该设计旨在确定该方案的最大耐受剂量（MTD）和剂量限制性毒性（DLT），并确定未来II期试验的剂量水平。
局部晚期且无法切除的胰腺癌患者接受45 Gy的放射治疗。初始UFT剂量为150 mg/m²/天，与亚叶酸钙90 mg/天同时服用，两者均分为每日3次剂量，共35天，与放疗同时进行。UFT剂量以50 mg/m²/天的增量递增。剂量限制性毒性（DLT）定义为尽管进行了医学干预仍出现3级或以上的恶心、呕吐或腹泻；或3级或以上的中性粒细胞减少/血小板减少；或3级或以上的肝毒性；或患者无法服用计划的UFT/亚叶酸钙的75%或更多；或放疗中断超过1周。当某一剂量在6名患者中的2名或更多患者中引起DLT时，UFT/亚叶酸钙的MTD被超过一个剂量水平。
5名可评估患者患有I期可切除疾病，但有病理淋巴结病。7名患者患有II期不可切除疾病。治疗依从性极佳。在UFT每日剂量为300 mg/m²时，我们注意到腹泻和血液学毒性极小，伴有轻度至中度恶心、厌食和疲劳。3名患者出现4级毒性：1名在第38天出现中性粒细胞减少，1名在第55天出现腹泻，1名在第15天出现呕吐。
口服UFT/亚叶酸钙和放射治疗为胰腺癌患者提供了一种可行的治疗选择。已知的主要毒性腹泻是可耐受的。本研究未达到MTD。我们目前的计划是将此扩展为一项I/II期试验，从UFT剂量300 mg/m²开始，并将其与临床药理学参数相关联。UFT的长生物利用度和口服给药的潜在益处与持续输注方案相比具有优势，且无导管和泵带来的额外发病率。
