聚乙二醇化重组人粒细胞刺激因子预防化疗后中性粒细胞减少的多中心随机对照Ⅱ期临床研究

A multicenter,randomized,controlled,phase Ⅱ clinical study of PEG-rhG-CSF for preventing chemotherapy-induced neutropenia in breast cancer patients

目的评价单次给予不同剂量聚乙二醇化重组人粒细胞刺激因子(PEG-rh G-CSF)预防乳腺癌患者化疗后引起的中性粒细胞减少的安全性与疗效。方法按随机、平行分组、开放性、阳性对照原则,将受试者按1∶1∶1∶1比例随机分为PEG-rh G-CSF 60μg/kg组、PEG-rh G-CSF100μg/kg组、PEG-rh G-CSF 120μg/kg组和rh G-CSF 5μg·kg^(-1)·d^(-1)组,所有患者采用TAC化疗方案。化疗21d为1个周期。结果 4度中性粒细胞减少的发生率比较显示,PEG-rh G-CSF 60μg/kg组高于rh G-CSF5μg·kg^(-1)·d^(-1)组,PEG-rh G-CSF 100μg/kg组和PEG-rh G-CSF 120μg/kg组与rh G-CSF 5μg·kg^(-1)·d^(-1)组相当。4度中性粒细胞减少的持续时间比较显示,PEG-rh G-CSF 60μg/kg组长于rh G-CSF5μg·kg^(-1)·d^(-1)组,PEG-rh G-CSF 100μg/kg组和PEG-rh G-CSF 120μg/kg组与rh G-CSF 5μg·kg^(-1)·d^(-1)组相当。PEG-rh G-CSF 60μg/kg组、PEG-rh G-CSF 100μg/kg组和PEG-rh G-CSF 120μg/kg组中性粒细胞减少性发热的发生率分别为7.0%、4.7%和11.9%,rh G-CSF 5μg·kg^(-1)·d^(-1)组为11.6%,差异无统计学意义(P=0.5043)。PEG-rh G-CSF 60μg/kg组、PEG-rh G-CSF 100μg/kg组和PEG-rh G-CSF120μg/kg组从化疗用药结束到中性粒细胞减少达到最低点的时间分别为(7.88±1.80)d、(7.88±2.12)d和(7.14±1.05)d,而rh G-CSF 5μg·kg^(-1)·d^(-1)组为(8.93±3.39)d,差异有统计学意义(P=0.0008)。PEG-rh G-CSF 60μg/kg组、PEG-rh G-CSF 100μg/kg组和PEG-rh G-CSF 120μg/kg组中性粒细胞减少从最低值达2.0×109/L以上所需要的时间分别为(3.44±3.08)d、(2.47±1.79)d和(2.90±2.54)d,rh G-CSF 5μg·kg^(-1)·d^(-1)组为(4.02±4.04)d,差异无统计学意义(P=0.0982)。PEG-rh G-CSF 60μg/kg组、PEG-rh G-CSF 100μg/kg组和PEG-rh G-CSF 120μg/kg组和rh G-CSF5μg·kg^(-1)·d^(-1)组不良事件的发生率分别为95.4%(41/43)、93.0%(40/43)、92.9%(39/42)和90.7%(39/43),差异无统计学意义(P=0.9202)。结论接受TAC化疗方案的乳腺癌患者于化疗后48 h单次注射PEG-rh G-CSF 100μg/kg,不良反应程度轻。单次注射PEG-rh G-CSF 100μg/kg与连续注射rh G-CSF 5μg·kg^(-1)·d^(-1)比较,预防化疗引起的中性粒细胞减少的安全性和疗效相当,推荐以PEG-rh G-CSF 100μg/kg进行Ⅲ期临床试验。

Objective The study was designed to evaluate the safety and efficacy of a single administration of different doses of pegylated recombinant human granulocyte colony-stimulating factor（ PEGrh G-CSF） in preventing chemotherapy-induced neutropenia in breast cancer patients,in order to provide the basis for the development of phase III clinical trial program. Methods According to the randomized,parallel-group,open,and positive control principle,all patients,who were undergoing TAC chemotherapy with 21 days / cycle,were randomized by1∶ 1∶ 1∶ 1 to receive PEG-rh G-CSF 60μg / kg,or PEG-rh G-CSF 100μg / kg,or PEG- rh G-CSF 120μg / kg,or rh G-CSF 5 μg·kg^（-1）·d^（-1）. Results In the incidence of grade 4 neutropenia,the value for the PEG-rh G-CSF 60μg / kg group was higher than that of the 5 μg·kg^（-1）·d^（-1）group,and the values for the PEG-rh G-CSF 100μg / kg group and the PEG-rh G-CSF 120μg / kg group were similar with that of the rh G-CSF 5 μg·kg^（-1）·d^（-1）group. Compared with 5 μg·kg^（-1）·d^（-1）group,the duration of grade 4 neutropenia of the PEG-rh G-CSF 60μg / kg group were longer,and that of the groups of PEG-rh G-CSF 100μg / kg and PEG-rh G-CSF 120μg / kg were similar with that in the rh G-CSF 5 μg·kg^（-1）·d^（-1）group. The incidence of febrile neutropenia in the PEG-rh G-CSF 60μg / kg group,PEG-rh G-CSF 100μg / kg group and PEG-rh GCSF 120μg / kg group were respectively 7. 0%, 4. 7% and 11. 9%, and 11. 6% in the rh G-CSF5 μg·kg^（-1）·d^（-1）group,the differences were not statistically significant（ P = 0. 5043）. The mean interval between the end of chemotherapy and the neutrophil nadir in the PEG-rh G-CSF 60μg / kg group,PEG-rh GCSF 100μg / kg group and PEG-rh G-CSF 120μg / kg group were respectively（ 7. 88 ± 1. 80） days,（ 7. 88 ±2. 12） days and（ 7. 14 ± 1. 05） days,and（ 8. 93 ± 3. 39） days in the rh G-CSF 5 μg·kg^（-1）·d^（-1）group,the differences were statistically significant（ P = 0. 0008）. And the mean interval from the neutrophil nadir to neutrophil count ≥2. 0 × 109/ L of the groups of PEG-rh G-CSF 60μg / kg,PEG-rh G-CSF 100μg / kg and PEG-rh G-CSF 120μg / kg were respectively（ 3. 44 ± 3. 08） days,（ 2. 47 ± 1. 79） days and（ 2. 90 ± 2. 54）days,compared with（ 4. 02 ± 4. 04） days in the rh G-CSF 5 μg·kg^（-1）·d^（-1）group,the differences were not statistically significant（ P = 0. 0982）. The incidence of adverse events in the test groups of PEG-rh G-CSF60μg / kg,PEG-rh G-CSF 100μg / kg and PEG-rh G-CSF 120μg / kg were 95. 4 %（ 41 /43）,93. 02%（ 40 /43） and 92. 86%（ 39 /42）,and 90. 7%（ 39 /43） in the control group of rh G-CSF 5 μg·kg^（-1）·d^（-1）,respectively,the differences were not statistically significant（ P = 0. 9202）. Conclusions In the breast cancer patients undergoing TAC chemotherapy,a single injection of PEG-rh G-CSF 100μg / kg from the 48 hours post-chemotherapy had mild adverse reactions. The safety and efficacy of a single injection of PEGrh G-CSF 100μg / kg in preventing chemotherapy-induced neutropenia were similar with that of daily injection of rh G-CSF 5 μg·kg^（-1）·d^（-1）,thus a single injection of PEG-rh G-CSF 100μg/kg can be recommended for the phase III clinical trial.