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作者：徐兵河，田富国，喻璟瑞，宋艳秋，石建华，张百红，张燕军，袁志平，吴穷，张清媛，南克俊，孙强，李维廉，胡建兵，毕经旺，孟春，戴红，蒋宏传，岳顺，曹邦伟，孙玉萍，王殊，佟仲生，沈朋，伍钢，唐利立，邓甬川，贾立群，沈坤炜，庄武，谢晓冬，伍尤华，陈琳 化疗为恶性肿瘤主要的治疗手段之一，中性粒细胞减少症是肿瘤化疗患者最常见的并发症，其发生会引起免疫功能下降，可能导致继发性感染。目前，治疗化疗引起的发热性粒细胞减少症在临床应用最有效、最广泛的药物为重组人粒细胞集落刺激因子（rhG-CSF）。rhG-CSF促使G0期粒系造血祖细胞进入G1期，进而增加粒细胞的生成，并促使其向外周血的释放，同时还可增强外周血成熟中性粒细胞的功能。但rhG-CSF通常需要多次用药才能得到改善，且药物相关不良反应比较明显，这无疑会延长患者的治疗周期，增加患者的身体和心理压力。聚乙二醇化重组人粒细胞刺激因子（PEG-rhG-CSF）是将rhG-CSF经单甲氧基聚乙二醇化学修饰后的制剂，具有单次用药即能缓解中性粒细胞缺乏的特点。但由于在国内的应用时间较短，临床医师对其用于治疗化疗后中性粒细胞减少的疗效尚存在较多疑问。为研究国产PEG-rhG-CSF的安全性和疗效，经中国食品药品监督管理局批准，中国医学科学院肿瘤医院作为临床研究负责单位，协同国内其他31家三级甲等医院，于2011年11月至2012年8月，对国产PEG-rhG-CSF进行了Ⅲ期多中心临床研究，现将结果报告如下。 目的：探讨聚乙二醇化重组人粒细胞刺激因子（PEG-rhG-CSF）用于预防乳腺癌和非小细胞肺癌患者化疗后引起中性粒细胞减少的安全性和疗效。 方法：根据随机、开放、平行对照原则，将受试者按1∶1∶1比例采用随机数字表法随机分为100μg/kg PEG-rhG-CSF组，6mg PEG-rhG-CSF组和5μg/kg rhG-CSF组。其中乳腺癌患者接受2个周期化疗，非小细胞肺癌患者根据病情接受1～2个周期化疗。全组患者采用TAC方案（多西他赛＋表柔比星＋环磷酰胺）或TA方案（多西他赛＋表柔比星）、多西他赛联合卡铂化疗方案，21d为1个周期。 结果：100μg/kg PEG-rhG-CSF组、6mg PEG-rhG-CSF组和5μg/kg rhG-CSF组患者3～4度中性粒细胞减少的持续时间比较，差异均无统计学意义（均P＞0.05）。100μg/kg PEG-rhG-CSF组、6mg PEG-rhG-CSF组和5μg/kg rhG-CSF组患者3～4度中性粒细胞减少的发生率分别为69.7%、68.4%和69.5%，差异无统计学意义（P=0.963）。100μg/kg PEG-rhG-CSF组、6mg PEG-rhG-CSF组和5μg/kg rhG-CSF组患者中性粒细胞减少性发热的发生率分别为6.1%、6.4%和5.5%，差异无统计学意义（P=0.935）。100μg/kg PEG-rhG-CSF组、6mg PEG-rhG-CSF组和5μg/kg rhG-CSF组患者不良反应的发生率分别为6.7%、4.1%和5.5%，差异无统计学意义（P=0.581）。 结论：行TAC方案或TA方案化疗的乳腺癌或非小细胞肺癌患者，于化疗后48h单次注射100μg/kg或6mg固定剂量PEG-rhG-CSF，不良反应发生率低，程度轻，疗效确切。与连续注射5μg/kg/drh G-CSF比较，预防化疗引起中性粒细胞减少的疗效相当，且更具优势。 美国Amgen公司研制的PEG修饰的长效rhG-CSF是第1个进入临床应用的PEG-rhG-CSF，临床已使用13年，其疗效显著，与rhG-CSF相比，PEG-rhG-CSF半衰期延长，具有中性粒细胞介导的自身调节机制，体内活性增强，不良反应较轻。 本研究结果显示，对于采用TAC方案和TA方案治疗的乳腺癌或非小细胞肺癌患者，于化疗后48h单次注射100μg/kg或6mg PEG-rhG-CSF，与连续注射5μg/kg/d rhG-CSF比较，安全性和疗效相当，且更具优势，这与国外报道的乳腺及胸部恶性肿瘤的Ⅱ期和Ⅲ期研究结果相符。 在本研究中，试验组采用了6mg和100μg/kg两种固定剂量给药方式。对于固定剂量给药，潜在的问题为可能不适合提供给体重较重或较轻的患者。有研究结果显示，6mg固定剂量在体重较重的患者中同样有效，且体重较重与较轻的患者发生3～4度中性粒细胞减少的持续时间无差异；6mg固定剂量组患者不良事件的发生率或严重程度与100μg/kg组和rhG-CSF组相比，差异均无统计学意义（均P＞0.05）。国外研究结果显示，PEG-rhG-CSF组给药后12d，所有入组患者的PEG-rhG-CSF血药浓度均＜2ng/ml，PEG-rhG-CS早期预防性用药可使中性粒细胞减少的发病率降低94%，减少80%静脉抗感染药物的使用，并降低住院率。国内研究结果也证实，单次应用PEG-rhG-CSF比多次应用rhG-CSF更能对中性粒细胞的增殖起到促进作用，更能明显缩短同步放化疗所致中性粒细胞缺乏状况的改善时间，从而降低因中性粒细胞缺乏所致临床风险的发生。与rhG-CSF相比，PEG-rhG-CSF在化疗剂量减少、中性粒细胞缺乏伴粒细胞减少发生率、院外感染引发的住院率、抗生素的使用率等方面，均有明显优势。 综上所述，PEG-rhG-CSF单次用药即可改善患者中性粒细胞减少，以保证患者按疗程进行抗肿瘤治疗，尤其是固定剂量给药，有效地简化了化疗诱导的中性粒细胞减少的管理，同时也减少了患者反复接受rhG-CSF注射的痛苦，给肿瘤患者的生活质量带来明显益处，具有良好的应用前景。 药品来源：PEG-rhG-CSF注射液和rhG-CSF注射液为齐鲁制药有限公司产品。 利益冲突：无 中华肿瘤杂志. 2016;38(1):23-27. Zhonghua Zhong Liu Za Zhi. 2016 Jan 23;38(1):23-7. A multicenter, randomized, controlled, phase III clinical study of PEG-rhG-CSF for preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer. Xu BH, Tian FG, Yu JR, Song YQ, Shi JH, Zhang BB, Zhang YJ, Yuan ZP, Wu Q, Zhang QY, Nan KJ, Sun Q, Li WL, Hu JB, Bi JW, Meng C, Dai H, Jiang HC, Yue S, Cao BW, Sun YP, Wang S, Tong ZS, Shen P, Wu G, Tang LL, Deng YC, Jia LQ, Shen KW, Zhuang W, Xie XD, Wu YH, Chen L. Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China. Department of Breast Surgery, Shanxi Province Cancer Center, Taiyuan 030013, China. Department of Oncology, Sichuan Provincial Tumor Hospital, Chengdu 610041, China. Cancer Center, the First Hospital of Jilin University, Changchun 130021, China. Department of Oncology, Cancer Hospital of Linyi City, Linyi 276001, China. Department of Oncology, Lanzhou General Hospital, Lanzhou Command, Lanzhou 730050, China. Department of Oncology, Shanxi Provincial Tumor Hospital Xi'an 710061, China. Department of Oncology, the Second People's Hospital of Yibin City, Yibin 644000, China. Department of Oncology, Cancer Hospital of Bengbu Medical College, Bengbu 233004, China. Department of Oncology, Cancer Hospital of Harbin Medical University, Harbin 150081, China. Department of Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China. Department of Oncology, the People's Hospital of Tianjin City, Tianjin 300121, China. Department of Oncology, the First People's Hospital of Yueyang City, Yueyang 414000, China. Cancer Therapy & Research Center, Jinan Military Command General Hospital, Jinan 250012, China. Department of Oncology, Central Hospital of Siping City, Siping 136000, China. Department of Oncology, Beijing Chaoyang Hospital of Capital Medical University, Beijing 100020, China. Department of General Surgery, Beijing Chaoyang Hospital of Capital Medical University, Beijing 100020, China. Department of Oncology, the First Hospital of Huai'an City, Nanjing Medical University, Nanjing 223300, China. Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Department of Oncology, Jinan City Central Hospital, Jinan 250015, China. Department of Breast Surgery, Peking University People's Hospital, Beijing 100044, China. Department of Breast Cancer, Cancer Hospital of Tianjin City, Tianjin 300060, China. Department of Chemotherapy, the First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China. Cancer Center, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Department of Breast Cancer, Xiangya Hospital, Central South University, Changsha 410008, China. Department of Oncological Surgery, the Second Affiliated Hospital, Zhejiang University, Hangzhou 310009, China. Department of Oncology, China-Japan Friendship Hospital, Beijing 100029, China. Department of Breast Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Department of Thoracic Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, China. Department of Oncology, the General Hospital of PLA Shenyang Military Command, Shenyang 110015, China. Department of Oncology, the First Affiliated Hospital of Nanhua University, Hengyang 421001, China. Department of Oncology, People's Hospital of Sichuan Province, Chengdu 610000, China. OBJECTIVE: To explore the safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer (NSCLC), and to provide the basis for clinical application. METHODS: According to the principle of open-label, randomized, parallel-group controlled clinical trial, all patients were randomized by 1∶1∶1 into three groups to receive PEG-rhG-CSF 100 μg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 μg/kg, respectively. The patients with breast cancer received two chemotherapy cycles, and the NSCLC patients received 1-2 cycles of chemotherapy according to their condition. All patients were treated with the combination chemotherapy of TAC (docetaxel+ epirubicin+ cyclophosphamide) or TA (docetaxel+ epirubicin), or the chemotherapy of docetaxel combined with carboplatin, with a 21 day cycle. RESULTS: The duration of grade 3-4 neutropenia in the PEG-rhG-CSF 100 μg/kg and PEG-rhG-CSF 6 mg groups were similar with that in the rhG-CSF 5 μg/kg group (P>0.05 for all). The incidence rate of grade 3-4 neutropenia in the PEG-rhG-CSF 100 μg/kg group, PEG-rhG-CSF 6 mg group, and G-CSF 5 μg/kg group were 69.7%, 68.4%, and 69.5%, respectively, with a non-significant difference among the three groups (P=0.963). The incidence rate of febrile neutropenia in the PEG-rhG-CSF 100 μg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 μg/kg group were 6.1%, 6.4%, and 5.5%, respectively, showing no significant difference among them (P=0.935). The incidence rate of adverse events in the PEG-rhG-CSF 100 μg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 μg / kg group were 6.7%, 4.1%, and 5.5%, respectively, showing a non-significant difference among them (P=0.581). CONCLUSIONS: In patients with breast cancer and non-small cell lung cancer (NSCLC) undergoing TAC/TA chemotherapy, a single 100 μg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF at 48 hours after chemotherapy show definite therapeutic effect with a low incidence of adverse events and mild adverse reactions. Compared with the continuous daily injection of rhG-CSF 5 μg/kg/d, a single 100 μg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF has similar effect and is more advantageous in preventing chemotherapy-induced neutropenia. PMID: 26796802 DOI: 10.3760/cma.j.issn.0253-3766.2016.01.005 |
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