聚乙二醇修饰脂质体阿霉素联合顺铂单次给药治疗晚期骨肉瘤的剂量递增试验  

Pegylated Liposomal Doxorubicin Combined with Cisplatin for Advanced Osteosarcoma:A Single-dose Dose-escalating Trial

作　　者：文习之[1] 潘求忠 翁德胜[1] 赵靖靖[1] 徐海荣[2] 黄真[2] 牛晓辉[2] 张星[1] WEN Xi-zhi;PAN Qiu-zhong;WENG De-sheng;ZHAO Jing-jing;XU Hai-rong;HUANG Zhen;NIU Xiao-hui;ZHANG Xing(Melanoma and Sarcoma Medical Oncology Unit,Biotherapy Center,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;Department of Orthopaedic Oncology Surgery,Jishuitan Hospital,Beijing 100000,China)

机构地区：[1]中山大学肿瘤防治中心生物治疗中心//黑色素瘤与肉瘤内科,广东广州510060 [2]北京积水潭医院骨肿瘤科,北京100000

出　　处：《中山大学学报（医学科学版）》2020年第4期582-588,共7页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：国家自然科学基金(81772863)。

摘　　要：【目的】为了探索聚乙二醇修饰脂质体阿霉素(PLD)联合顺铂在骨肉瘤化疗中PLD的最大耐受剂量(MTD)。【方法】纳入经病理确诊的转移性或不可切除的骨肉瘤患者14例,接受1个周期的PLD联合顺铂方案化疗。PLD分为3个剂量水平(40、50和60 mg/m^2,第1天),每个剂量组计划入组3例患者,按3+3方法进行剂量递增;顺铂(100 mg/m^2,分成4 d使用)的剂量保持不变;每21 d一个疗程。受试者在化疗结束后48 h接受粒细胞刺激因子预防性升白细胞治疗。按照NCI CTCAE v4.0统计不良反应。【结果】纳入研究的患者中有男性9例,女性5例,中位年龄为20(14~43)岁。在PLD剂量递增至60 mg/m^2剂量组,入组的2例患者均出现3级口腔黏膜炎合并4级中性粒细胞减少性发热,达到剂量限制性毒性,因此下调一个剂量等级。在50 mg/m^2剂量组,一共入组9例患者,仅1例患者出现剂量限制性毒性,表现为4级血小板减少持续大于3 d。在入组的所有患者中,观察到的3~4级不良反应为中性粒细胞下降(12例,12/14)、血小板减少(7例,7/14)、贫血(4例,4/14)及口腔黏膜炎(2例,2/14)。所有不良反应经对症、支持治疗后均可缓解,无治疗相关死亡。【结论】在PLD联合顺铂治疗晚期骨肉瘤的化疗方案中,PLD的最大耐受剂量为50 mg/m^2,主要剂量限制性毒性为口腔黏膜炎及中性粒细胞减少性发热,不良反应经对症治疗后可缓解。【Objective】To explore the maximum tolerated dose(MTD)of pegylated liposome doxorubicin(PLD)when combined with cisplatin as a modified regimen for osteosarcoma.【Methods】A total of 14 patients with pathologically confirmed metastatic or unresectable osteosarcoma received one cycle of PLD combined with cisplatin therapy.The study used a traditional 3+3 design,with three PLD dose levels(40,50,and 60 mg/m^2,day 1).It was designed to recruit three patients initially at each dose level.Cisplatin was given at a dose of 100 mg/m^2(administered within four days)for each pa⁃tients.Patients received prophylactic granulocyte stimulating factor therapy 48 h after chemotherapy.Toxicities were documented according to the the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0(NCI CTCAE v4.0)【.Results】Of the 14 patients,9 were male and 5 female,with a median age of 20 years(range 14~43).Both of the patients at dose level of 60 mg/m^2 experienced dose-limiting toxicity(DLT)(grade 3 oral mucositis and grade 4 neu⁃tropenic fever).Only 1 of the 9 patients at dose level of 50 mg/m^2 experienced DLT(grade 4 thrombocytopenia lasting for more than 3 days)and thus the MTD was 50 mg/m^2.Most common grade 3~4 adverse events across all cohorts included neutropenia(12 cases,12/14),thrombocytopenia(7 cases,7/14),anemia(4 cases,4/14)and oral mucositis(2 cases,2/14).All the adverse events were relieved after symptomatic and supportive treatment.No treatment-related death was ob⁃served.【Conclusions】For advanced osteosarcoma,when combined with cisplatin,the MTD of PLD was 50 mg/m^2.The main DLT was oral mucositis and neutropenic fever.The adverse events can be relieved after symptomatic treatment.

关 键 词：骨肉瘤 聚乙二醇脂质体阿霉素 Ⅰ期临床试验 

分 类 号：R738[医药卫生—肿瘤]