PURPOSE:To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. EXPERIMENTAL DESIGN:Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m(2) every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP < or = upper limit of normal (ULN)], mild dysfunction group B (bilirubin < or = ULN, ULN < AST < or = 2.5 x ULN, or ULN < AP < or = 5 x ULN), moderate dysfunction group C (ULN < bilirubin < or = 3.0 mg/dL, AST > 2.5 x ULN, or AP > 5 x ULN), severe dysfunction group D (bilirubin > 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. RESULTS:Dose escalation of single-agent oxaliplatin to 130 mg/m(2) was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months. CONCLUSIONS:Oxaliplatin at 130 mg/m(2) every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.

译文

目的:确定奥沙利铂在肝功能不全患者中的毒性,药代动力学和最大耐受剂量,并为该患者人群制定奥沙利铂剂量的正式指南。
实验设计:60例肝功能可变的成年癌症患者接受了静脉内注射。奥沙利铂每3周从60到130 mg / m(2)不等。根据肝功能障碍的程度将患者按总胆红素,天冬氨酸转氨酶(AST)和碱性磷酸酶(AP)的水平分为五个队列:对照组A [胆红素,AST和AP <或=正常上限( ULN)],轻度功能障碍B组(胆红素<或= ULN,ULN 2.5 x ULN或AP> 5 x ULN),严重功能障碍D组(胆红素> 3.0 mg / dL,任何AST和任何AP)和肝移植E组(任何胆红素,任何AST和任何AP)。在三名患者的队列中增加剂量,并测定尿液和血浆超滤液的铂浓度。
结果:在所有队列中,单药奥沙利铂的剂量递增都可耐受130 mg / m(2)。铂清除率与任何肝功能检查均不相关。在56例可诊断为喉癌和宫颈腺癌的可评估患者中,有2例的局部反应持续了3个月和5.5个月。
结论:在所有肝功能受损的患者中,每3周服用130 mg / m(2)的奥沙利铂具有良好的耐受性。肝功能不全的患者未提示降低单药奥沙利铂的剂量。

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