PURPOSE:To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. EXPERIMENTAL DESIGN:Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m(2) as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m(2) bolus i.v. and leucovorin 20 mg/m(2) i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m(2) and 5-FU to 500 mg/m(2). RESULTS:Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3-4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. CONCLUSIONS:Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.

译文

目的:确定吉非替尼联合伊立替康,5-氟尿嘧啶(5-FU)和亚叶酸(IFL)联合治疗吉非替尼的最大耐受剂量(MTD),毒性,疗效和药代动力学(PK)。
实验设计:起始剂量为吉非替尼250 mg /天,口服不间断,伊立替康100 mg / m(2),静脉内(i.v.)90分钟输注,5-FU 400 mg / m(2)静脉内推注。和亚叶酸钙20 mg / m(2)静脉注射在21天周期的第1天和第8天。剂量增加包括将吉非替尼增加至500 mg,然后将伊立替康增加至125 mg / m(2),将5-FU增加至500 mg / m(2)。
结果:24例患者接受了治疗。事实证明,起始剂量是MTD,因为尝试增加吉非替尼或化学治疗剂的剂量会导致剂量限制的毒性。胃肠道疾病和骨髓抑制是主要的毒性。但是,只有1/17(6%)的MTD患者出现了严重的腹泻(3-4级),而仅2例(12%)的患者出现了严重的中性粒细胞减少。在接受MTD的10/17例患者中出现部分反应,另外5例病情稳定。中位无进展生存期和总生存期分别为12.2和26.6个月。在10例接受MTD治疗的患者中,吉非替尼的稳态PK不受IFL的影响,吉非替尼似乎也没有影响伊立替康或5-FU的PK。
结论:吉非替尼可以与间歇性IFL每周计划安全地合并使用。有希望的活动的证据应鼓励对表皮生长因子受体酪氨酸激酶抑制剂(如吉非替尼)与多药化疗联合治疗转移性结直肠癌进行进一步的临床评价。

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