Gill P S, Mitsuyasu R T, Montgomery T, Huang J, Cabriales S, Testa M, Espina B M, Levine A M, Miles S A
Department of Internal Medicine, University of Southern California School of Medicine, Los Angeles, USA.
Cancer J Sci Am. 1997 Sep-Oct;3(5):278-83.
To define the maximum tolerated dose of doxorubicin when combined with fixed doses of bleomycin, vincristine, zidovudine, and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) in patients with advanced AIDS-related Kaposi's sarcoma.
Twenty male patients were treated with zidovudine at doses of either 100 or 200 mg by mouth every 4 hours, and cytotoxic chemotherapy with bleomycin 10 U/m2 and vincristine 1.4 mg/m2 by vein every 2 weeks. Four successive cohorts received fixed doses of doxorubicin given intravenously every 2 weeks: two cohorts each received 10 mg/m2 (levels 1, 2) or 20 mg/m2 (levels 3, 4). The first cohort received rhGM-CSF at a dose of 10 micrograms/ kg, given subcutaneously on days 2 through 11 (level 1). Due to toxicity, the dose of rhGM-CSF was reduced to 5 micrograms/kg (levels 2, 3) and then to 2.5 micrograms/kg (level 4).
The dose-limiting toxicity was severe neutropenia, occurring in 10 patients. Severe neutropenic episodes occurred after a median of three cycles of chemotherapy, with the nadir occurring after 14 days (median). Moderate neutropenia occurred in 14% of all cycles administered. Constitutional toxicities of moderate or greater severity occurred in four patients. Five of 10 patients at a doxorubicin dose of 20 mg/m2 (levels 3 and 4) experienced severe neutropenia. Thus, doxorubicin at 10 mg/m2, with BV (bleomycin, vincristine chemotherapy), zidovudine (100 mg five times daily), and rhGM-CSF (5 micrograms/kg/day), was defined as the maximum tolerated dose.
The maximum tolerated dose of doxorubicin is 10 mg/ m2 every 2 weeks when given in combination with BV chemotherapy, zidovudine, and rhGM-CSF. While the addition of rhGM-CSF at doses of 2.5 to 5 micrograms/kg decreased the duration of neutropenia, it did not prevent the occurrence of severe neutropenia from combined myelotoxic therapy.
确定阿霉素与固定剂量的博来霉素、长春新碱、齐多夫定及重组人粒细胞巨噬细胞集落刺激因子（rhGM-CSF）联合应用于晚期艾滋病相关卡波西肉瘤患者时的最大耐受剂量。
20名男性患者每4小时口服100或200mg齐多夫定，并每2周静脉注射10U/m²博来霉素和1.4mg/m²长春新碱进行细胞毒性化疗。连续四个队列每2周静脉给予固定剂量的阿霉素：两个队列各接受10mg/m²（1、2级）或20mg/m²（3、4级）。第一个队列在第2至11天皮下给予10μg/kg剂量的rhGM-CSF（1级）。由于毒性反应，rhGM-CSF剂量减至5μg/kg（2、3级），然后减至2.5μg/kg（4级）。
剂量限制性毒性为严重中性粒细胞减少，10名患者出现该情况。严重中性粒细胞减少发作发生在化疗中位三个周期后，最低点出现在14天（中位时间）。所有给药周期中有14%出现中度中性粒细胞减少。4名患者出现中度或更严重程度的全身毒性。10名接受20mg/m²阿霉素剂量（3、4级）的患者中有5名出现严重中性粒细胞减少。因此，阿霉素10mg/m²联合博来霉素、长春新碱化疗、齐多夫定（每日5次，每次10mg）及rhGM-CSF（5μg/kg/天）被确定为最大耐受剂量。
阿霉素与博来霉素、长春新碱化疗、齐多夫定及rhGM-CSF联合应用时，最大耐受剂量为每2周10mg/m²。虽然给予2.5至5μg/kg剂量的rhGM-CSF可缩短中性粒细胞减少的持续时间，但并不能预防联合骨髓毒性治疗导致的严重中性粒细胞减少的发生。
