临床肿瘤学杂志

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腔内应用重组人血管内皮抑制素和/或顺铂治疗恶性胸腹腔积液的前瞻性、随机对照、全国多中心Ⅲ期临床研究

秦叔逵1,杨柳青1,梁军2,程颖3,谭清和4,毕经旺5,王理伟6,胡冰7,石建华8,孙国平9,白玉贤10,陶敏11,郭伟剑12,鲁冰13,张贺龙14   

  1. 1 南京中医药大学附属八一医院全军肿瘤中心 2 北京大学国际医院肿瘤科 3 吉林省肿瘤医院胸部肿瘤内科 4 南通市肿瘤医院肿瘤内科 5 解放军济南总医院肿瘤科 6 上海交通大学医学院附属仁济医院肿瘤科 7 安徽省立医院肿瘤科 8 临沂市肿瘤医院肿瘤内科 9 安徽医科大学附属第一医院肿瘤科 10 哈尔滨医科大学附属肿瘤医院内科 11 苏州大学附属第一医院肿瘤科 12 复旦大学附属肿瘤医院肿瘤内科 13 同济大学附属肺科医院肿瘤科 14 第四军医大学唐都医院肿瘤科
  • 收稿日期:2017-02-12 修回日期:2017-02-20 出版日期:2017-03-31 发布日期:2018-06-06
  • 通讯作者: 梁军

Intra-pleural injection of recombinant human endostatin and/or cisplatin in treatment of malignant hydrothorax and ascites: A multicenter randomized controlled trial

QIN Shukui, YANG Liuqing, LIANG Jun, CHENG Ying, TAN Qinghe, BI Jingwang, WANG Liwei, HU Bing, SHI Jianhua, SUN Guoping, BAI Yuxian, TAO Min, GUO Weijian, LU Bing, ZHANG Helong   

  1. Cancer Center of PLA, the 81st Hospital of PLA, Nanjing University of Chinese Medicine
  • Received:2017-02-12 Revised:2017-02-20 Online:2017-03-31 Published:2018-06-06
  • Contact: LIANG Jun

摘要: 目的 观察和确证腔内应用重组人血管内皮抑制素注射液(恩度)和/或顺铂治疗恶性胸腹腔积液的有效性和安全性。方法 2011年1月至2014年1月, 在全国14家大型医院肿瘤中心开展前瞻性、随机、平行对照、多中心的Ⅲ期临床研究(ClinicalTrials.gov注册号:NCT01327235)。入选中等量以上恶性胸腹腔积液患者,随机分为A组(恩度单药组)、B组(顺铂单药组)和C组(恩度联合顺铂组)。3组均在充分穿刺抽液或引流后给药。A组腔内注射恩度,45 mg/次(胸腔)或60 mg/次(腹腔);B组腔内注射顺铂,40 mg/次;C组为上述两种药物联合应用,剂量相同;3组给药时间均为d1、d4、d7,连用3次为1个疗程。参照WHO标准,严密观察客观缓解率(ORR)、疾病进展时间(TTP)、生活质量(QOL)以及Karnofsky功能状态评分(KPS),并评价安全性。结果 全分析集(FAS) 共纳入317例,其中A组105例,B组104例,C组108例;符合方案集(PPS) 共纳入275例,其中A组98例,B组89例,C组88例。FAS和PPS分别有298例和273例可评价疗效。FAS中A、B、C 3组的ORR分别为48.51%、46.39%和63.00% (P=0.0373),两两比较,C组较A、B组高(P=0.0189)。其中,既往无腔内治疗、胸腔积液、女性、无全身化疗、积液初治、充分引流、血性积液以及非胃癌来源的患者,应用恩度具有更好的ORR(P<0.05或P<0.01)。对于血性积液, A、C组ORR分别为71.05%和80.00%,均显著优于B组的45.16% (P=0.0090);其中,对于血性胸腔积液,A、C组ORR分别为71.42%和88.88%,均显著优于B组的40.00% (P=0.0013)。A、B、C组的中位TTP分别为68.869天、44.951天和69.030天 (P=0.0121);两两比较,A、C组的中位TTP均长于B组 (P=0.0240, P=0.0046)。第3次和第6次用药后,A组QOL评分和KPS评分获得改善人群的比例均显著高于B、C组(P<0.05或P<0.01)。安全性方面,317例均进入安全分析集分析。A组不良事件发生率显著低于B组(P=0.0005),B、C组之间差异无统计学意义(P=0.2866)。结论 采用恩度腔内给药治疗恶性胸腹腔积液具有较好疗效,尤其是对血性积液;恩度与顺铂联合应用具有协同作用,可以进一步提高疗效,延长TTP,改善患者QOL,且不增加化疗药物的不良反应,值得临床上积极推广应用。

Abstract:

Objective To evaluate the clinical efficacy and safety of intrapleural injection of recombinant human endostatin (endostar) and/or cisplatin in treatment of malignant hydrothorax and ascites. Methods The multicenter, randomized controlled study was conducted in 14 Chinese nationwide large hospitals from January 2011 to January 2014(Clinical Trials:NCT01327235.). A total of 317 patients with more than moderate amount of pericardial effusion malignant hydrothorax and ascites were randomly divided into group A (endostar group, n=105), group B (cisplatin group, n=104) and group C (endostar combined cisplatin group, n=108). After puncture and drainage, endostar 45 mg per time by intrathoracic injection or 60 mg per time by intraperitoneal injection was performed in group A. Cisplatin, 40 mg per time by intrapleural injection on day 1, 4 and 7, was administrated in group B. Endostar and cisplatin were administrated in group C. All three groups of patients were administrated on day 1, 4 and 7, and three times as a course. The main outcomes were objective response rate (ORR), time to disease progression (TTP), quality of life (QOL) and Karnofsky performance status (KPS), as well as the drug safety. Results A total of 317 patients were included in full analysis set (FAS) (group A with 105 cases, group B with 104 cases, group C with 108 cases), and 275 patients were included in perprotocol set (PPS) (group A with 98 cases, group B with 89 cases, group C with 88 cases). There were 298 cases and 273 cases qualified for evaluation on drug efficacy in FAS and PPS respectively. There was a significant difference in ORR among three groups (A: 48.51%, B: 46.39%, C: 63.00%, P=0.0373), and ORR was higher in group C than that in groups A and B (P=0.0189). Patients without intracavitary treatment history, with hydrothorax, female, without systemic chemotherapy, with initial treatment on effusion, with sufficient drainage, with hemorrhagic effusion and without diagnosis of gastric carcinoma had better outcome in ORR after treatment (P<0.05 or P<0.01). In those with hemorrhagic effusion, the ORRs in groups A and C were significantly higher than that of group B (A: 71.05%, B: 45.16%, C: 80.00%, P=0.0090). And in those with hemorrhagic pleural effusions specifically, the ORRs in groups A and C were significantly higher than that of group B (A: 71.42%, B: 40.00%, C: 88.88%, P=0.0013). The median TTP was 68.869 d, 44.951 d and 69.030 d in group A, B and C, respectively, with a significant difference (P=0.0121), and was shorter in group B than that in group A and C (P=0.0240, P=0.0046). The proportion of patients with improved QOL and KPS in group A was higher than that in group B and C after the third and sixth administration, respectively (P<0.05 or P<0.01). The incidence of adverse events was lower in group A than that in group B (P=0.0005), but no significant difference was shown between group B and C (P=0.2866).
Conclusion Intra-pleural injection of endostar is potentially effective in treatment of patients with malignant hydrothorax and ascites, especially those with hemorrhagic effusion. It shows a synergistic effect with cisplatin in improving the clinical efficacy, TTP and QOL, but without increasing the risk of adverse reactions. It is worth to be widely applied in clinical practice further.

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