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

Treatment of chemotherapy-induced neutropenia with pegylated recombinant human granulocyte colony-stimulating factor: a multi-center randomized controlled phaseⅡclinical study

目的比较聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)和重组人粒细胞集落刺激因子(rhG-CSF)预防化疗后中性粒细胞减少症的有效性和安全性。方法采用多中心随机自身交叉对照,初治恶性肿瘤患者接受2个周期相同方案的化疗,其中试验周期给予PEG-rhG-CSF100μg/kg皮下注射一次,对照周期每日一次皮下注射rhG-CSF5μg/kg,直至外周血中性粒细胞绝对值(ANC)达低谷后连续两次检查≥5·0×109/L。结果入组104例肿瘤患者,在103个试验周期和100个对照周期中,ANC<1·5×109/L的发生率分别为30·00%和20·00%,持续时间分别为2·39d和2·35d;ANC<0·5×109/L的发生率分别为5·80%和4·00%;抗生素使用率分别为13·59%和13·00%(以上差异均无统计学意义);发热性中性粒细胞减少发生率均为0。受试药和对照药的不良反应均为骨骼肌肉疼痛、乏力、发热、头晕等,发生率与严重程度相似。结论PEG-rhG-CSF一次给药的疗效和不良反应与rhG-CSF多次给药相似。

Objective To compare the efficacy and safety of daily administration of recombinant human granulocyte colony-stimulating factor （rhG-CSF） , and a single subcutaneous injection of pegylated recombinant human granulocyte colony-stimulating factor （PEG-rhG-CSF） , a sustained-duration rhG-CSF, in chemotherapy-induced neutropenia. Methods In the present randomized, open-label, match and crossover study, enrolled 104 patients with previously untreated non- small cell lung cancer （ NSCLC）, breast cancer or non-Hodgkin＇s lymphoma and with normal bone marrow function from 13 centers were randomly divided into 2 matched groups, AB and BA group. Each patient received two cycles of chemotherapy of identical regimen. In the study cycle, the patients received a single subcutaneous injection of PEG-rhG-CSF 100 μg/kg on day 3; and in control cycle, daily subcutaneous infection of rhG-CSF 5 μg·kg^-1·d^-1 began on day 3 and continued for 14 days or until the absolute neutrophil coant （ANC） became t〉5.0 ×10^9/L, twice after it degreased to the nadir. Efficacy and safety parameters were monitored. Results The incidence rates of ANC 〈 1.5 ×10^9/L in the 103 evaluable study cycles and 100 evaluable control cycles were 30.00% and 20.00% with the duration of 2.39 days and 2.35 days respectively. The incidence rates of grade 3 neutropenia were 7.77% and 7.00% ; and that of grade 4 neutropenia were 5.80% and 4.00% respectively in the trial and control cycles. However, all the difference mentioned above did not reached statistical significance. None of the patients experienced febrile neutropenia. The ANC nadir was （ 7.55 ± 5.25） ×10^9/L and （8.42 ± 5.57 ） ×10^9/L （ P = 0. 257 ） respectively after receiving PEG-rhG-CSF and rhG-CSF. Compared with that of rhG-CSF group, the ANC profile of PEG-rhG-CSF group exhibited limited ＂overshoot＂ of neutrophils after the nadir. Subgroup analysis according to disease type yielded similar results. The safety profiles of the PEG-rhG-CSF and rhG-CSF groups were similar. Musculoskeletal pain or arthralgia occurred in 16.5% of the study cycles and 26.00% of the control cycles （ P = 0. 963 ）, mostly mild or moderate. Other adverse effects such as fever, fatigue, dizziness, gastrointestinal effects and injection-site pain, were transient and easily manageable. Conclusion A single subcutaneous injection of PEG-rhG-CSF 100 p.g/kg provides neutrophil support and a safety profile comparable to regimen of daily subcutaneous injection of rhG-CSF 5 μg·kg^-1·d^-1 in Chinese patients receiving a variety of myelosuppressive chemotherapy regimens.